Living with a chronic condition that may or may not be characterized by exacerbating and remitting symptoms along with a constellation of other diagnoses and symptoms that may or may not be related possibly in the context of some kind of trauma is becoming more common or at least discussed more openly. I see this presentation in clinic at least once a week. Allopathic physicians are becoming more open to the idea that a patient’s complex presentation may not be just one diagnosis, and they are also beginning to believe that complex presentations are also not just manifestations of malingering–finally. As medical research advances in various fields, certain diagnoses are now possible that were not forty years ago. Hereditary Alpha Tryptasemia (HαT) is one of these diagnoses–only just recently discovered in the early 90s.

What is Hereditary Alpha Tryptasemia (HαT)?

• HαT is common and has been found to be present in approximately 5% of people in Western Europe and the United States.
• HαT is caused by extra inherited copies of the gene TPSAB1 that makes extra α-tryptase and leads to high tryptase in peripheral blood at baseline.
• If you have HαT, there is a 50% chance your children will inherit HαT.
• An estimated 90% of individuals in the general population with increased baseline serum tryptase (BST) levels have HαT.
• While certain tryptases stored inside mast cells is believed to contribute to allergy symptoms, the version of tryptase (pro-tryptases) that can be detected in people regularly at baseline – and that is elevated in HαT – has no known function in human health or disease.
• Many symptoms have been associated with HαT, but it is difficult to prove that symptoms are caused, or even contributed to, by HαT because it is so common.
• As many as 2 out of 3 individuals with HαT are believed to have few if any symptoms that would lead to them being diagnosed with this genetic trait.
• HαT has been shown to increase the frequency and/or severity of anaphylaxis in specific settings including following certain insect stings and in patients without identifiable causes for anaphylaxis (idiopathic) and/or the clonal mast cell disease systemic mastocytosis (SM).
• A small increase in the number of mast cells in bone marrow and the lining of the GI tract has been consistently shown among symptomatic individuals with HαT.
• Patients with SM are more likely to have HαT compared to the general population, but this may result from an increase in symptoms seen in patients that have both SM and HαT.
• HαT does not appear to be a risk factor for classical irritable bowel syndrome (IBS) but does appear to modify some of the symptoms in patients with this disorder (source).

What are the signs and symptoms of HαT?

HαT is classified as a mast cell disease. Hereditary Alpha Tryptasemia Syndrome (HαTS) is the clinical manifestation complete with signs and symptoms of the inherited genetic trait called Hereditary Alpha Tryptasemia. You may, however, see the disease itself referred to as just Hereditary Alpha Tryptasemia (HαT) or Hereditary Alpha Tryptasemia Syndrome (HαTS).

“The two initial studies describing families with HαT published in 2014 and 2016, identified multi-system complaints or symptoms among family members with HαT that were co-inherited with elevated BST (baseline serum tryptase). 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 hyper-mobility and retained primary teeth
• symptoms suggestive of autonomic nerve dysfunction such as inappropriate changes in blood pressure or heart rate” (source)

It is important to note that HαTS is associated with:

• More severe anaphylaxis and mast cell mediator symptoms in certain clonal and non-clonal mast cell-associated disorders
• 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” (source)

How is HαT diagnosed?

The easiest way to diagnose HαT is through genetic testing via blood testing:

“…A specialized test that uses a technology called droplet digital polymerase chain reaction (ddPCR) is available for clinical use from a Clinical Laboratory Improvement Amendments (CLIA)-certified clinical laboratory: https://genebygene.com/tryptase/  The assay run for clinical use is the same assay that was developed by Lyons et al. in 2016. Tryptase genotyping by ddPCR should be considered in symptomatic individuals with elevated basal serum tryptase levels, and is currently the only test available to confirm the diagnosis of HαT…The first step in diagnosing HαT involves having your physician measure a total serum tryptase level. In the large majority of individuals with HαT, serum tryptase levels are over 8 ng/mL. Most genetic sequencing techniques available for clinical use are unable to determine the number of α– and β-tryptase encoding sequences anyone has” (source).

How is HαT treated?

HαT or HαTS is treated very similarly to other mast cell diseases–symptomatically. So, it depends on your symptoms.

I was diagnosed with HαTS two years ago after a very long and winding health journey. As it turns out, it runs in my family. I was the first person to be tested, but after I was diagnosed I asked my mother to pursue testing. She also tested positive. My mother has connective tissue problems, two autoimmune diseases, chronic migraines, chronic gastrointestinal problems, and mental health diagnoses. I have an autoimmune diagnosis, idiopathic anaphylaxis, several severe food allergies, bee and wasp allergies, connective tissue problems, GI problems that were diagnosed as celiac disease, autonomic nerve dysfunction, and chronic migraines. It certainly ticks all the HαTS boxes.

Receiving a mast cell disease diagnosis took ages. I have seen numerous neurologists, rheumatologists, allergists, gynecologists, gastroenterologists, and a hematologist. I’ve undergone numerous medical diagnostic tests ranging from upper and lower GIs, endoscopies, MRIs, CT scans, and hundreds of blood tests to a colonoscopy, a bone marrow biopsy, a lumbar puncture, and multiple EKGs and EEGs. My second allergist suspected a mast cell disease, but it was the third allergist I saw who confirmed it through genetic testing and a bone marrow biopsy (the bone marrow biopsy is done to rule out mastocytosis). In the end, I was diagnosed with Hereditary Alpha Tryptasemia Syndrome along with an autoimmune connective tissue disorder-SLE adjacent, and chronic migraine disease. Those diagnoses are still not entirely agreed upon by my treating physicians either. A former neurologist is convinced that I have CNS vasculitis associated with SLE, and my rheumatologist does not agree. And, I can’t be sure, but it intuitively feels like all of these diagnoses leads back to HαTS because it is a multi-systemic disease (and I haven’t even mentioned Histamine Intolerance and DAO (diamine oxidase) deficiency). Does it matter? The treatment approaches are still going to be symptom-based. If you have a headache, treat the symptoms. If you have anaphylaxis, treat the symptoms. Sometimes this approach works very well. Sometimes it doesn’t. My medical journey is not unusual. Actually, it’s fairly representative of most people dealing with multiple symptoms across systems.

From a Conventional Medical Treatment Perspective (mixed with some functional medicine), a treatment protocol for Hereditary Alpha Tryptasemia Syndrome accompanied by a mast cell activation event might be:

Daily Protocol:

1. cetirizine (Zyrtec): 10 mg BID or twice daily. After anaphylaxis episodes: 20 mg BID or 2 pills twice daily. To prevent a bi-phasic reaction, it is possible to take dose at 10 mg TID or three times a day.
2. quercetin (Weng, Z., Zhang, B., Asadi, S., Sismanopoulos, N., Butcher, A., Fu, X., Katsarou-Katsari, A., Antoniou, C., & Theoharides, T. C. (2012). Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity in humans. PloS one, 7(3), e33805. https://doi.org/10.1371/journal.pone.0033805)
3. luteolin (Theoharides, T. C., Stewart, J. M., Hatziagelaki, E., & Kolaitis, G. (2015, July 3). Brain “fog,” inflammation and obesity: Key aspects of neuropsychiatric disorders improved by Luteolin. Frontiers in neuroscience. Retrieved March 22, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490655/
4. berberine (Fu S, Ni S, Wang D, Fu M, Hong T. Berberine suppresses mast cell-mediated allergic responses via regulating FcɛRI-mediated and MAPK signaling. Int Immunopharmacol. 2019 Jun;71:1-6. doi: 10.1016/j.intimp.2019.02.041. Epub 2019 Mar 9. PMID: 30861392.)
5. Vitamin C, D, E (Kakavas, S., Karayiannis, D., & Mastora, Z. (2021). The Complex Interplay between Immunonutrition, Mast Cells, and Histamine Signaling in COVID-19. Nutrients, 13(10), 3458. https://doi.org/10.3390/nu13103458)
6. Zinc (Kakavas, S., Karayiannis, D., & Mastora, Z. (2021). The Complex Interplay between Immunonutrition, Mast Cells, and Histamine Signaling in COVID-19. Nutrients, 13(10), 3458. https://doi.org/10.3390/nu13103458)
7. Omega-3 fatty acids (animal or plant-derived) (Kakavas, S., Karayiannis, D., & Mastora, Z. (2021). The Complex Interplay between Immunonutrition, Mast Cells, and Histamine Signaling in COVID-19. Nutrients, 13(10), 3458. https://doi.org/10.3390/nu13103458)

After the anaphylaxis, mast cell flare, or exacerbation has passed, the cetirizine can be stopped and the other supplements continued. If the anaphylaxis or flare is severe, I add 25 mg Benadryl BID (twice daily) to the protocol. The example listed above is my current protocol along with some other herbs and nutraceuticals. My allergist prefers I stay on cetirizine all the time, but antihistamines are anticholinergics (they affect acetylcholine which is our most abundant neurotransmitter), and long-term anticholinergic use can affect long-term memory and is also linked to dementia. I prefer not to take anticholinergic medications if I don’t absolutely require them, but sometimes I do require them. That’s when I take them.

Please note that you must be careful when taking berberine as it inhibits certain liver enzymes which can affect blood levels of certain prescription drugs that use those enzymes. So, be sure to discuss any berberine supplementation with your doctor. A website that I frequently use is www.drugs.com. It’s very handy for looking up drug side effects and pharmacokinetics. Another extremely useful site is www.naturalmedicines.therapeuticresearch.com. You can find an abundance of information on herbal drugs and supplements on this site, and I use it frequently when looking up patient supplement information and writing case studies.

There are, of course, dietary interventions that we can undertake, and Eastern and functional medicine have an entirely different perspective (that is a post I will write soon).

Some useful takeaways:

1. If you have a constellation of symptoms that do not seem to be related and multiple diagnoses, it is possible that your symptoms and diagnoses actually are related.
2. Stress and trauma of all kinds can manifest in the body and cause symptoms of illness, pain, and disease. Just because these symptoms are related to trauma and/or stress does not make the illness, pain, and disease any less valid and/or serious.
3. Trying to do anything while living with a chronic condition is very difficult and trying to solve your own health conditions, weird symptoms, and pain on your own is daunting. I encourage you to reach out to a provider who is equipped to help you–even if that means putting your name on a waiting list, consulting with a functional medicine doctor, seeing a doctor who practices integrative medicine, or even getting in front of a new physician who can look at your case with fresh eyes. There are very hard-working practitioners out there who are dedicated to the well-being and healing of their patients. In my case, I saw five neurologists before I found a good one, two allergists before I found one who took the extra steps to diagnose me correctly, and three gynecologists before landing on a gem!

Wishing you all good health,

MJ