Hereditary Alpha Tryptasemia May Act as a Disease Modifier in Inflammatory Bowel Disease

Introduction: Hereditary alpha tryptasemia (HaT, ICD-10 D89.44) is an autosomal dominant genetic trait present in up to 6% of individuals of European ancestry. Approximately, 1/3 of individuals with this genetic trait are symptomatic. Typically, individuals with symptomatic HaT present with skin, nerve, or GI manifestations and a tryptase of >8 ng/ml. HaT is independently associated with an increased risk of anaphylaxis. Diagnosis is confirmed by performing digital droplet PCR to confirm extra copies of TPSAB1 ( >4) which is located on chromosome 16. Major GI symptoms include esophageal reflux, abdominal pain, diarrhea, constipation, and gastrointestinal food sensitives. We have previously shown that HaT is associated with increased mast cell numbers, accelerated epithelial pyroptosis (inflammatory cell death), and increased class switch memory B cells in the small intestine in absence of a gut inflammatory disorder. Methods: Our teritary academic center follows large, well characterized HaT population (n=134). Within this population, we noted that 8 individauls had been diagnosed with either Crohn’s or ulcerative colitis. To better understand the impact of HaT on inflammatory bowel disease (IBD), we gathered data on age of IBD diagnosis, number of advanced IBD therapies tired, numbers of surgeries,average basal serum tryptase (BST) levels, and response to current IBD therapy. Results: Of the 8 individuals with HaT and IBD, 7 had Crohn’s disease and 1 had pancolonic ulcerative colitis. 50% of the individuals in this cohort were diagnosed prior to age 20. Five of eight patients had had a bwel resection for treatment of Crohn’s. On average, the individuals in this cohort had failed at least 3 advanced IBD therapies. The average BST was 17.3 ng/ml (Non IBD HaT cohort has average BST of 14). Six of eight patients experienced endoscopic remission on a JAK inhibitor (tofacitinib or upatacitanib). Two of eight patients experienced clinical improvement with ustekinumab. Conclusion: Our data indicates that IBD appears to be more common and severe in individuals with a HaT (IBD prevalence in the general population is estimated to be 1.3% but in this HaT cohort, it is 6%). Future studies are needed to understand whether or not HaT acts as a disease modifier in IBD.