Medical maxims abound: What’s common is common, but you’re also more likely to encounter an uncommon presentation of a common disease than a common presentation of an uncommon one. With that in mind, this viewpoint is devoted to both the former and the latter. The inspiration was a patient of mine whose digestive symptoms improved after elimination of alpha gal allergens supported by corresponding lab studies. It’s anecdotal but as you read, you’ll see that this has been described by others and so, consider this piece “food for thought.”
Many allergic conditions are limited to the gastrointestinal (GI) tract (eg, eosinophilic esophagitis [EoE] or eosinophilic gastroenteritis [EG]). The presentation of EoE is hard to miss, especially if routine screening is performed for any visit. A few simple questions (eg., dysphagia, eating slowly, cutting food into small bites) usually suffices. The latter can be harder to identify but still is “on the radar” of the astute practicing allergist.
Another food allergy presenting with purely GI symptoms is food protein-induced enterocolitis syndrome (FPIES). The first event may not be suspected to be allergic; viral gastroenteritis or food poisoning is usually the first thought, especially in adult patients. For infants with a profound reaction with hypovolemia, FPIES should be included in the differential diagnosis. Cases of chronic FPIES (in formula-fed) infants have also been described. [1] As with EoE and EG, these conditions are not immunoglobulin E (IgE)-mediated so a skin test or radioallergosorbent test (RAST) are of no diagnostic utility. Confirmation should be made with biopsy, and the culprit food — if it exists — should be determined by food challenge or elimination (followed by serial endoscopy and biopsy). In my adult allergy practice, shellfish is the most common trigger. Not surprisingly, I have yet to meet a patient willing to undergo a food challenge.
More challenging is the situation in which an allergic condition that typically manifests with systemic symptoms presents only with GI symptoms. It’s tempting to diagnose food intolerance (eg, lactose or fructose) or irritable bowel syndrome in some of these patients, but others may in fact be in our “wheelhouse.”
Bradykinin-mediated angioedema may present only with bowel angioedema. Triggers of uncontrolled bradykinin release include drugs (ACE-inhibitors) and C1-esterase deficiency. Examples include hereditary angioedema (HAE), an autosomal dominant inherited disease that may also occur de novo. Even less common is acquired C1-INH deficiency due to autoantibodies or monoclonal gammopathies. Although the skin is certainly the most common site of swelling, bowel angioedema occurs in 89% of HAE attacks, and in 49% is the only manifestation. While the more severe attacks causing bowel obstruction are more likely to appear to be a surgical emergency, milder episodes may mimic irritable bowel syndrome.2 The GI symptoms of bradykinin-mediated angioedema are often nonspecific, and include distention, cramping, nausea, vomiting, and diarrhea. If there is any doubt, a C4 is a simple screening test for HAE.
Alpha-gal sensitivity (AGS), an IgE-mediated anaphylactic reaction, most commonly occurs hours after eating red meat (ie, beef, veal, lamb) but not poultry. The etiology, as identified by the renowned Dr Thomas Platts-Mills, is the bite of the lone star tick triggering sensitization to cross-reacting carbohydrate moieties. Anaphylactic episodes are not as hard to diagnose in the occasional meat eater (and in my experience it’s even easier in a patient with a history of tick bites or visiting/residing in endemic areas), but what of the habitual meat eater? Is every episode anaphylactic or might the symptoms be more chronic and less dramatic? Diagnosis is established by IgE to alpha-gal (AG), a commercially-available test.
Not only do AG patients react to the meats but also to other bovine proteins. Between 70%-90% of patients with AGS are reported to have anti-bovine milk IgE.3 (In particular, the patients had IgE to whey.) In a large US study of 2500 patients with AGS, 10%-20% experienced delayed abdominal and/or urticaria due to milk.4 In a Swedish study of 128 patients, 74.2%, had GI symptoms but only 6% experience GI symptoms alone.5 A study of two clinics in the southeast US (Lone Star Tick endemic area), looked at 16 AG IgE patients with isolated GI symptoms, the most common of which were abdominal pain, nausea, and diarrhea, and were more episodic than chronic.6 The patients did not report an association with meat ingestion but most recalled a tick bite. With meat avoidance, all patients improved, and some completely. Patients with AG who experienced isolated GI symptoms had much lower mean AG IgE (0.61) than AG patients with anaphylaxis. Of the patients who avoided meat with symptomatic improvement, six had recurrent GI symptoms upon meat rechallenge and one had anaphylaxis.
Gastrointestinal anaphylaxis is a term used for patients whose sole manifestation of an IgE-mediated allergic reaction. In my opinion, this is a bit of a misnomer if not a confusing term. Either way, it is a fairly uncommon event. The reaction can have both immediate and delayed symptoms including diarrhea and abdominal cramping.
The allergist might be the last stop on the long journey of a patient with unexplained GI symptoms. It’s best to resist the temptation to run the patient-requested and often unnecessary food skin test panel, but rather dig deeper into the history and consider uncommon alternatives. They may be more common than we realize.
References:
1. Baker MG, Sampson HA. Recent trends in food protein-induced enterocolitis syndrome (FPIES). J Allergy Clin Immunol. 2023 Jan;151(1):43-46. doi: 10.1016/j.jaci.2022.11.002. PMID: 36608982.
2. Jalaj S, Scolapio JS. Gastrointestinal manifestations, diagnosis, and management of hereditary angioedema. J Clin Gastroenterol. 2013 Nov-Dec;47(10):817-23. doi: 10.1097/MCG.0b013e31829e7edf. PMID: 24141983.
3. Perusko M, Apostolovic D, Kiewiet MBG, et al. Bovine γ-globulin, lactoferrin, and lactoperoxidase are relevant bovine milk allergens in patients with α-Gal syndrome. Allergy. 2021;76(12):3766-3775. doi:10.1111/all.14889.
4. 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.
5. Kiewiet MBG, Apostolovic D, Starkhammar M, Grundström J, Hamsten C, van Hage M. Clinical and Serological Characterization of the α-Gal Syndrome-Importance of Atopy for Symptom Severity in a European Cohort. J Allergy Clin Immunol Pract. 2020;8(6):2027-2034.e2. doi:10.1016/j.jaip.2020.02.016.
6. Croglio MP, Commins SP, McGill SK. Isolated Gastrointestinal Alpha-gal Meat Allergy Is a Cause for Gastrointestinal Distress Without Anaphylaxis. Gastroenterology. 2021;160(6):2178-2180.e1. doi:10.1053/j.gastro.2021.01.218
Stadtmauer reports no relevant financial relationships.
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