The goal of this post is to explore potential connections between Mast Cell Activation Syndrome (MCAS), a common (but highly underdiagnosed) condition, and Hereditary Angioedema (HAE), a rarer disease. In order to do that, let’s start with a little background on HAE.

According to the US Hereditary Angioedema Association (USHAEA), “HAE symptoms include edema (swelling) in various parts of the body including: hands, feet, face and airway. Patients often suffer excruciating abdominal pain, nausea, and vomiting caused by swelling of the intestinal wall.” Swelling in other areas (such as the groin and the brain) have also been reported. Airway swelling is a life-threatening emergency that can cause death by asphyxiation. The mortality rate for HAE was 30% before treatment became available in 2008.¹ It’s estimated that between 1 in 10,000 and 1 in 50,000 people have HAE, classifying it as a rare disease.¹

Most types of HAE are caused by a lack of a protein called C1-esterase inhibitor which regulates the production of bradykinin, a chemical mediator that causes swelling and the movement of fluid outside the tissues. HAE can also be caused by a mutation in the protease factor XII. A subgroup of HAE patients are significantly impacted by estrogen levels.

There are three types of HAE,

Type I: caused by low levels of C1 inhibitor protein

Type II: caused by normal or elevated levels of dysfunctional C1 inhibitor protein

Type III: caused by mutation in gene for coagulation factor XII; sometimes called “estrogen-dependent” angioedema

Simple blood tests at baseline and during attacks assist in diagnosis. Serum C4 levels are typically low during attacks / between attacks in patients with HAE and C4 is considered a cost-effective and reliable screening test.

Though the majority of HAE cases have a family history, approximately 25% of cases occur with no known family history,² which is attributed to a spontaneous mutation of the C1-inhibitor gene at conception. There’s a 50% chance that children will inherit HAE from an affected parent. Symptoms may be present before age seven, and 66% of patients reported that they became symptomatic with noticeable attacks starting by age 13.¹ The majority of patients will have HAE attacks emerge or worsen by their teenage years or early 20’s. It’s common for patients to remain undiagnosed, sometimes for decades, and particularly in the case of abdominal attacks, patients often experience un-necessary surgeries and multiple mis-diagnoses.

HAE influences the complement system and episodes of pain and swelling typically last 2-5 days at a time. Research notes that the severity of the pain associated with HAE has been indistinguishable from that of labor/delivery and appendicitis in many cases.³ The swelling of the airway is very distinct from anaphylaxis; with HAE, patients tend to experience a slower and more gradual airway swelling (without the presence of hives) that does not respond to antihistamines or epinephrine.

What does HAE have to do with MCAS?

In Part One, I described my personal experience with episodes of abdominal, throat (and occasionally face/extremity) angioedema. I am a patient who has been clinically diagnosed with both conditions, and since my diagnosis I’ve encountered a number of other patients in the same predicament. Coincidental?… I am starting to think not!

Abdominal angioedema has also been connected to mast cell activity and is considered a type of “third spacing.” “Third spacing” refers to the movement of interstitial fluid into the tissues where it does not belong.⁴ Many patients with MCAS anecdotally report third spacing in their abdominal cavity. This does not, however, mean that all patients experiencing this phenomenon have HAE, though it can result in a very similar painful ascites-like abdominal swelling that can take several days to resolve. Sometimes the pain and swelling are so severe that patients appear to be in the third trimester of pregnancy.

Image from the US Hereditary Angioedema Association

“Third spacing” can cause dangerous complications such as circulatory shock, life threatening airway swelling, severe dehydration, impaired organ function, and gastrointestinal obstructions from swelling.⁴ “Third spacing” may be triggered by anaphylaxis in some cases for patients with MCAD⁴ (though anaphylaxis is not the mechanism with HAE episodes, which are considered non-allergic). Abdominal angioedema has been associated with the use of angiotensin-converting enzyme inhibitors (ACE inhibitors) used to manage high blood pressure.⁵ However, there are numerous other mechanisms that can trigger attacks of “third spacing.”

Patients with HAE report a plethora of triggers, from environmental factors and toxins (like exposure to cleaning supplies or a water damaged building) to drops in barometric pressure, vibrations from car and airplane travel, lack of sleep, certain foods or beverages, exercise, surgery, insect bites or stings, minor trauma, illness such as the flu or common cold, hormonal fluctuations, dental procedures, and emotional stress (both positive emotions like excitement and negative emotions like anger).¹

While certain mast cell mediators could potentially be responsible for “third spacing,” in an interview in September of 2017, Dr. Afrin told me that he believes that episodes of acute abdominal pain/bloating may be more connected to dysautonomia of the bowel muscles.⁶ If you’re familiar with the Driscoll Theory⁷, the Vagus nerve plays a very important role in bowel motility and could be connected to this problem. If GI transit time is delayed and the intestinal contents are left sitting stagnant, this could in theory cause a putrefaction-like process to occur which could influence levels of certain mast cell mediators and inflammation in the intestinal tissue, further exacerbating pain and swelling. This is one theory that connects abdominal angioedema and MCAD, but it has not been researched.

Just for kicks, I conducted a very informal social media poll in early 2018 on a Facebook HAE group page (2,550 members) and found that, out of the 39 people who responded, 17 did not have MCAS, 16 had never heard of it, 3 did have both MCAS and HAE, and 3 people with HAE suspected that they had MCAS but had not been tested for it. So, if we remove people who were not familiar with what symptoms are typical of MCAS, about 13% had clinical diagnoses of both, and 26% had either an MCAS diagnosis or self-described signs of MCAS. It would be interesting to conduct some real research in this area and determine if there are epidemiological connection between the different types of HAE and MCAS. Of course, this was one snapshot in time of a small sample size via a voluntary social media poll – but still, it raised more personal curiosity on the topic.

I was able to locate some data on associations between HAE and Systemic Mastocytosis, which is a type of Mast Cell Activation Disease that is pathologically and clinically distinct from MCAS. A 2016 study found that patients with HAE were nearly 5 times more likely to have the co-morbid diagnosis of Systemic Mastocytosis compared to the general population.⁸ This implies that may be a deeper connection between mast cells and HAE than we currently realize.

Most experts conclude that the two conditions can certainly “feed off” each other if a patient has the clinical diagnosis of both HAE and MCAS. Unfortunately and unsurprisingly, I couldn’t find any epidemiological data on connections between MCAS and HAE, as MCAS research is in it’s infancy. Currently, it appears that we’re unable to draw concrete conclusions about whether one may contribute to another, though it’s likely that mast cell activation can trigger increased bradykinin secretion which can increase the severity or duration of HAE attacks.

There are some theoretical connections between HAE and MCAS that relate to mast cell mediators such as bradykinin and heparin.  Research has shown that heparin released by mast cells contributes to increased vascular permeability in patients with HAE.⁹ Specifically, heparin contributes directly to bradykinin formation via activation of the complement system following IgE-mediated mast cell activation. In animal studies, mice with C1 INH-deficiency had earlier vascular leakage that was longer-lasting and increased in quantity following exposure to heparin, when compared to mice without C1 INH-deficiency.⁹

Visual explanation of mechanisms between mast cell activation, heparin and bradykinin-mediated edema presented by Oschatz et al. (2011)

The authors concluded, “Our studies offer a rationale for immediate adverse heparin effects: we show that heparin initiates bradykinin generation by activating the FXII-driven contact system in vivo and that this pathway contributes to MC (mast cell)-driven inflammation, hypotension and edema.”⁹   In addition to bradykinin-specific mechanisms, heparin appears to play a more global role in regulating mast cell granule content and function, (particularly with proteases, which are fully active enzymes that can contribute to immediate tissue injury during mast cell degranulation) so it’s possible that self-regulatory feedback loops could contribute to dysfunctional mechanisms in patients that have both HAE and MCAS.^10,11 

Patients with MCAS often report low blood pressure and drops in blood pressure that are associated with pre-syncope and syncope during mast cell degranulation. Heparin and the combination of heparin with other substances (such as dextran sulfate in animals, which activates the complement system) have been associated with a drop in blood pressure that can be reversed with Icatibant, a medication used to treat HAE attacks. ⁹ Icatibant (brand name Firazyr) is a selective bradykinin b2 receptor antagonist.

Researchers have also identified allergen-sensitized mast cells as an initiator of pathological edema formation in the mouse model of HAE.⁹  Folllowing this discovery, researchers had 38 HAE patients in Switzerland complete a survey identifying attack triggers. Eleven out of thirty-eight patients (29%) reported that swelling was associated with allergic reactions to foods. 8% reported insect toxin-based triggers, and 3% noted that a drug triggered attacks.⁹ 

The findings that associated food reactions with HAE attacks support the theory that mast cell-mediated reactions may be a key component to symptoms in some HAE patients. However, anecdotally it appears that most patients with HAE do not respond favorably to mast cell-targeting medications. Indeed, an angioedema symptom response to antihistamines and/or steroids is a clinical sign that the patient does not have HAE (but could have an “acquired” or “allergic” angioedema).¹² This, to me, indicates that MCAS may not cause HAE attacks, but perhaps the connection is that certain mast cell mediators supplement the pathways that are already occurring in HAE patients to trigger an increase in other factors such as the severity or duration of attacks.

Logically, one could imagine how a patient who is already predisposed to elevated levels of bradykinin (genetically) could see an increase in symptoms if their mast cells were hyper-sensitive or susceptible to increased activation via a number of different triggers. In theory, this could create a vicious cycle between heparin, the complement system, bradykinin, mast cells, edema, pain and inflammatory responses. Furthermore, HAE attacks involve great deals of emotional stress and physical pain which may very likely exacerbate a repeated pattern of increased mast cell degranulation.

Or perhaps the two conditions share other common variables as the root underlying issue. From personal experience I can attest that my HAE attack frequency has coincided with my increasing intolerance to toxins (especially odors such as secondhand cigarette smoke, candles, perfumes, cleaning supplies, laundry detergent, etc). I believe that a sluggish liver and a high toxin load is a main factor in my personal example of both HAE-type attacks and mast cell reactions, both of which occur frequently (and very distinctly from each-other in terms of symptom characteristics). I have spoken with many HAE patients who have severe intolerances to the same toxin-based products; environmental sensitivities and reactions are also highly reported in patients with MCAS. Perhaps toxin accumulation and stress on the liver is another factor that triggers both HAE attacks and mast cell reactions via distinctly different mechanisms. Going a step further, it would be interesting to investigate if certain viral and bacterial loads (such as Lyme Disease and Epstein-Barr Virus) predispose patients to the development of detoxification issues and subsequent development (or a flare-up in baseline) of either condition. Hopefully future research will investigate this area.

In summary, while HAE attacks are distinct from anaphylactic attacks in both mechanism and characteristics, it appears that mast cell mediators and mast cell activation can trigger an increase in factors that may contribute to the intensity or frequency of HAE attacks. This may very well be confounded by the presence of dysautonomia, viruses, bacteria and other co-morbidities or dysfunctional processes that may impair aspects such as gastrointestinal motility or system-wide detoxification. I can only conclude that hopefully we’ll have more concrete research on potential mechanisms between the two diseases in the future. I strongly encourage patients who experience recurrent episodes of severe third spacing to investigate the possibility of HAE or idiopathic angioedema with their medical team.

Thanks for reading this post in honor of Rare Disease Awareness Day (Feb. 28). If you have any theories or research explanations for other potential mechanisms between HAE & MCAS, please send them my way via email or leave a comment!

In case you missed it, you can read Part One here: HAE & MCAS: Part I

References:

1. United States Hereditary Angioedema Association: Accessed from https://www.haea.org on February 23, 2018.
2. Banerji A. Hereditary angioedema: classification, pathogenesis, and diagnosis. Allergy Asthma Proc. 2011; 32(6):403-7.
3. Staubach P, Eckardt AJ. Symptoms, Course, and Complications of Abdominal Attacks in Hereditary Angioedema Due to C1 Inhibitor Deficiency. American J GastroEnterol. 2006; 101:619-627.
4. Third Spacing by Lisa Klimas: Accessed from http://www.mastattack.org/2014/07/third-spacing/ on February 23, 2018.
5. Mutnuri S, Khan A, Variyam EP. Visceral angioedema: an under-recognized complication of angiotension converting enzyme inhibitors. Postgraduate Medicine. 2015;127:215-217.
6. Afrin, Lawrence. Interviewed in person on September 16, 2017 in St. Cloud, Minnesota.
7. The Driscoll Theory by Dr. Diana Driscoll: Accessed from http://www.prettyill.com/ on February 23, 2018.
8. Stevens, Chris, Joseph C. Biedenkapp, Robert Mensah, Yung H. Chyung, and Burt Adelman. “Hereditary Angioedema Is Associated with Neuropathic Pain, Systemic Lupus Erythematosis and Systemic Mastocytosis in an Analysis of a Health Analytics Claims Database.” Journal of Allergy and Clinical Immunology137, no. 2 (2016): AB75.
9. Oschatz C, Maas C, Lecher BD, Jansen T, Bjorkqvist J, Tradler T, Sedlmeier R, Burfeind P, Cichon S, Hammershmidt S, Muller-Esterl W, Wuillemin WA, Nilsson G, Renne R. Mast Cells Increase Vascular Permeability by Hepain-Initiated Bradykinin Formation In Vivo. Immunity. 2011;34(2):258-268.
10. Humphries, Donald E., Guang W. Wong, Daniel S. Friend, Michael F. Gurish, Wen-Tao Qiu, Chifu Huang, Arlene H. Sharpe, and Richard L. Stevens. “Heparin is essential for the storage of specific granule proteases in mast cells.” Nature400, no. 6746 (1999): 769.
11. Dai, Hongyan, and Ronald J. Korthuis. “Mast cell proteases and inflammation.” Drug Discovery Today: Disease Models8, no. 1 (2011): 47-55.
12. Cicardi, Marco, W. Aberer, A. Banerji, M. Bas, J. A. Bernstein, K. Bork, T. Caballero et al. “Classification, diagnosis, and approach to treatment for angioedema: consensus report from the Hereditary Angioedema International Working Group.” Allergy 69, no. 5 (2014): 602-616.

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