Introduction: IgE antibodies to the oligosaccharide galactose-α-1,3-galactose (α-gal) are an important cause of allergic reactions to mammalian meat and other mammal-derived products. The symptoms of α-gal syndrome (AGS) can involve urticaria or anaphylaxis, but increasingly we are aware that GI tract symptoms, including diarrhea, are also a major feature of AGS. Pancreatic exocrine insufficiency (PEI) is a common cause of diarrhea and treatment involves the use of pancreatic replacement enzymes (PRE). PRE are porcine derived and contain α-gal. Patients receiving PRE who are α-gal IgE positive are at risk for allergic reactions and GI symptoms due to α-gal sensitivity. Here we reviewed patients with suspected PEI and concomitant α-gal IgE sensitization in the practice of one gastroenterologist in Virginia. Methods: Retrospective chart review was carried out using inclusion criteria of i) diarrhea, ii) low fecal elastase (< 200 μg/g feces), and iii) α-gal IgE sensitization ( >0.10 kU/L). Results: 15 patients were identified with mean fecal elastase of 123 and median IgE α-gal level 0.96 (Table). 9 improved off of mammalian-containing food products and 3 of these did not require PRE. 11 patients received PRE. Of 5 patients with pre-existing systemic allergy symptoms to mammalian meat, 1 improved off of mammalian products and did not require PRE, 1 had increased diarrhea with Creon and was lost to follow up, 1 tolerated Creon with pruritus, 1 experienced hives from Creon but successfully underwent office-based desensitization, and 1 patient avoided PRE due to the severity of allergy symptoms. 6 patients without the classic cutaneous allergy symptoms of AGS tolerated PRE, though 1 developed some urticaria. Conclusion: In this series of 15 patients with suspected PEI who had concomitant α-gal IgE >0.1 kU/L, 60% improved with removal of α-gal containing products from the diet and 20% did not require PRE. Of the 11 patients who were treated with ongoing PRE, 3 experienced urticaria and 1 had increased diarrhea, but none had severe allergic symptoms. In our experience, patients who are sensitized to α-gal can usually tolerate PRE. Practitioners should also be aware that worsening diarrhea during PRE treatment could be a consequence of α-gal-related hypersensitivity, rather than medication non-compliance. Recognition of AGS superimposed upon PEI will allow improve management in this complex patient population. Table 1. - Clinical data from 15 patients with suspected pancreatic exocrine insufficiency diagnosed with concomitant α-gal syndrome Characteristics Total Cohort (n=15) Age, mean years (range) 59.5 (19-80) Sex, female, n (%) 9 (60%) Race, Caucasian, n (%) 15 (100%) Fecal Elastase, mean μg/g fecal material (range) 123 (49-183) IgE to α-gal, median kU/L (range) 0.96 (0.41-26.1) Diarrhea Severity recorded, n (%) 13 (87%) Mild, 0-4 stools per day, n (%) 4 (31%) Moderate, 5-8 stools per day, n (%) 6 (46%) Severe, >8 stools per day, n (%) 3 (23%) Improvement with mammalian avoidance, n (%) 9 (60%) Treated with PRE, n (%) 11 (73%) Creon, n (%) 10 (91%) Zenpep, n (%) 1 (9%) Allergy Symptoms attributed to PRE, n (%) 4 (36%) Urticaria, n (%) 3 (27%) Diarrhea, n (%) 1 (9%)