Signs, Symptoms & Triggers

Mast cells can be activated through both IgE and non-IgE-related mechanisms, resulting in the release of mediators, such as tryptase, histamine, heparin, leukotrienes and prostaglandins.¹ This activation can occur in a healthy person, for example in response to a mosquito bite, and in patients with both mastocytosis and mast cell activation syndrome (MCAS). Patients with mastocytosis have extra mast cells that can activate and release their mediators, in addition to the possibility of mast cells that may more readily release mediators, resulting in increased mediator-induced symptoms. Patients with MCAS may also have mast cells that are signaled to release their mediators more easily; this may depend on genetics, tissue location of the reacting mast cells, the trigger that initiates the response, or even coexisting conditions.^{2, 3} Symptomatology can arise from both mediator release and/or from mast cell proliferation, accumulation and infiltration in tissues, depending on the form of mast cell disease. Triggers can be common to both patients with mastocytosis and MCAS, but may be different for each patient.

Symptoms and Triggers of Mast Cell Activation (Mastocytosis and MCAS)

Signs and Symptoms of Mast Cell Proliferation, Accumulation and Infiltration (Mastocytosis)

Symptoms associated with Hereditary alpha tryptasemia (HαT)

Jonathan J. Lyons, MD

Affiliations: Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.

Funding statement: This research was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, NIH. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

The two initial studies describing families with HαT published in 2014 and 2016, identified multisystem complaints or symptoms among family members with HαT that were coinherited with elevated BST. In some cases, similar symptoms were also present in other family members who did not have HαT but in those individuals, symptoms were less severe. Symptoms included: skin flushing, itching and in some cases recurrent hives were present; abdominal pain, bloating and other irritable bowel syndrome (IBS)-like symptoms; anaphylaxis to several causes, most notably to stinging insects (e.g., yellow jackets, wasps, hornets, and honeybees); connective tissue abnormalities including joint hypermobility and retained primary teeth; and symptoms suggestive of autonomic nerve dysfunction such as inappropriate changes in blood pressure or heart rate.

Tryptase is principally made by cells responsible for allergic symptoms – primarily tissue mast cells, and to a lesser extent cells called basophils that circulate in peripheral blood. Because of this, tryptases are rarely measured or studied in patients who do not present with allergic symptoms, diseases or reactions. So far, all published studies involving individuals with HαT have also been from institutions which focus on genetic and/or mast cell-related disorders, creating both detection and referral biases inherent in many of symptoms that have been associated with HαT.

Only one small group of individuals within a larger study has queried symptoms from unselected, ostensibly healthy, adults. Among the nine individuals that were identified with HαT agnostically, one-third (3/9) were found to have minimal symptoms, one-third (3/9) had a few symptoms, and the remaining one-third (3/9) reported lots of symptoms. These symptoms were similar to the group of symptoms that have been reported in multiple studies and included: anaphylaxis in particular in response to stinging insects, connective tissue abnormalities such as joint hypermobility and retained primary dentition, symptoms of autonomic dysfunction, eosinophilic gastrointestinal disease, food intolerances, chronic pain and fatigue. Studies are ongoing in order to test these prior associations. Of these, only systemic reactions to stinging insects, skin flushing and itching, IBS-like abdominal complaints, retained primary teeth, and symptoms of autonomic dysfunction – measured using a scoring system – were significantly increased among individuals with HaT.

HαT is associated with more severe anaphylaxis and mast cell mediator symptoms in certain clonal and non-clonal mast cell-associated disorders

In the first study to describe the genetic cause for HαT, systemic immediate allergic reactions, or anaphylaxis to stinging insects (most commonly Hymenoptera species) were found to be nearly ten times more common among individuals prospectively identified with HαT. This finding prompted an follow-up NIH-led collaboration to study two large groups of patients with Hymenoptera venom-triggered anaphylaxis (HVA) from Italy and Slovenia. The frequency of HαT among venom allergic individuals presenting with severe anaphylaxis was found to be approximately double, compared to the general population or those who had milder reactions. Importantly, the overall number of venom allergic patients with HαT was comparable to the general population. This suggested that HαT is unlikely to be a risk factor for venom allergy, but in venom allergic patients, roughly doubles the chance of having a bad systemic reaction.

Initial reports describing HαT also reported that up to 20% of people with this trait in symptomatic families had a history of anaphylaxis. These reactions occurred not only following insect stings, but also were triggered by foods, radiocontrast media, allergy shots, and in some cases happened spontaneously (an event called idiopathic anaphylaxis). In order to determine whether HαT might increase the rate of anaphylaxis, the same NIH-led team examined the frequency of HαT among groups of patients with systemic mastocytosis (SM) and idiopathic anaphylaxis. In both groups HαT was found to be approximately 3-times more common than the general population. A subsequent large European study also found that HαT was about 3-times more common among patients with SM compared to the general population. Importantly, in both the NIH and European studies, the frequency of anaphylaxis in patients with SM and HαT was also approximately doubled when compared to patients with SM alone.

The increased number of SM patients with HαT compared to the general population is likely due in part to a detection bias, where individuals with both HαT and SM are more likely to be highly symptomatic, and thus more likely to come to medical attention. However, a number of studies have now demonstrated moderate increases in mast cell numbers in the bone marrow and GI lining – called epithelium – of symptomatic individuals with HαT when compared to healthy volunteers or patients with similar symptoms who do not have HαT. These findings suggest that having extra α-tryptase may somehow affect mast cell growth or survival in some way. Potential mechanism(s) underlying these findings are an active area of research. Despite these interesting research findings, and in part because SM is quite rare, simply having HαT is not associated with a clinically relevant increase in the risk for developing SM.

In addition to anaphylaxis, HαT has been associated with more severe mast cell mediator-associated symptoms in European SM patients based upon a validated questionnaire-based scoring system. Interestingly, symptom severity demonstrated a gene-dosage effect – where increasing TPSAB1 copy number was associated with more symptoms and higher symptom scores. While one small study in the UK did not observe a similar gene-dosage effect among allergy patients in a clinical practice, potentially due to the small number of patients with more than one extra TPSAB1 gene copy in this study, a similar gene-dosage effect on symptom severity was also reported in the first and largest study of symptomatic individuals with HαT that has been published to date.

Gastrointestinal complaints and immune cell differences are distinct from IBS in HαT patients with GI

While irritable bowel syndrome (IBS)-like symptoms have been frequently reported among symptomatic individuals with HαT, a recent study of a well-characterized large group of patients with IBS failed to demonstrate any increase in the frequency of individuals with HαT, arguing strongly again HαT being a risk factor for classical IBS. In this same study, the authors went on to show that among individuals with GI symptoms and HαT an unusual kind of inflammation called pyroptosis was seen in the lining of the gastrointestinal system at a comparable amount to what is typically seen in patients with the gluten-associated inflammatory disorder called Celiac disease and seen in asymptomatic patients with a treated inflammatory bowel disease (IBD) called Crohn’s disease. These inflammatory changes were associated with immunologic changes both in the lining of the GI system as well as similar changes that could be detected in peripheral blood, but the significance of these immunologic differences remain uncharacterized. One interesting change was the finding of increased numbers of mast cells, which confirmed a prior publication reporting a similar finding. How HαT or increased α-tryptase expression might lead to any of these findings remains speculative.