The Provider Primer Series: Management of mast cell mediator symptoms and release

Mast cell disease is largely managed by treatment of symptoms induced by mast cell mediator release or by interfering with mediator release.

The following tables detail treatment recommendations described in literature by mast cell disease key opinion leaders. Please refer to source literature for future details on dosing, duration, and so on. These are not my personal recommendations and any and all treatment decisions must be made by a medical professional familiar with the patient.

Second and third generation H1 antihistamines are preferred to exclude neurologic symptoms accompanying use of first generation H1 antihistamines. However, first generation H1 antihistamines are sometimes used by mast cell patients and in the setting of anaphylaxis.

In advanced and aggressive forms of mast cell disease, use of cytoreductive agents, chemotherapy, and, very rarely, hematopoietic stem cell transplant may be considered.

Table 1: Primary treatment options (consensus) for mast cell mediator symptoms or release described in literature
Class Target Intended actions of target Symptoms associated with target Reference
H1 antihistamines (second or third generation preferred) H1 histamine receptor Promotes GI motility, vasodilatation and production of prostaglandins, leukotrienes and/or thromboxanes (via release of arachidonic acid) and nitric oxide  Hypotension, decreased chronotropy, flushing, angioedema, pruritis, diarrhea, headache, urticaria, pain, swelling and itching of eyes and nose, bronchoconstriction, cough, and airway impingement Valent 2007[i], Picard 2013[ii], Molderings 2016[iii], Hamilton 2011[iv]
H2 antihistamines H2 histamine receptor Release of gastric acid, vasodilation, smooth muscle relaxation, and modulates antibody production and release in various immune cells Increased chronotropy, increased cardiac contractility, hypertensioni, bronchodilation, increased presence of Th2 T cells, increasing IgE production Valent 2007, Picard 2013, Molderings 2016, Hamilton 2011
Mast cell stabilizer (cromolyn) Unknown targets to modulate electrolyte trafficking across the membrane to deter mast cell degranulation 

 

 

 

Unclear. Mast cell mediator release regulates many physiologic functions, including allergy response, immune defense against pathogens, angiogenesis, and tissue remodeling. In theory, all symptoms derived from mast cell mediator release. Research has demonstrated decreased release of mediators including histamine and eicosanoids. Valent 2007, Picard 2013, Molderings 2016, Hamilton 2011

 

Table 2: Primary treatment options (non-consensus) for mast cell mediator symptoms or release described in literature
Class Target Intended actions of target Symptoms associated with target Reference
Leukotriene receptor antagonists Leukotriene receptor Smooth muscle contraction, immune cell infiltration, production of mucus Bronchoconstriction, airway impingement, overproduction of mucus, pruritis, sinus congestion, runny nose Hamilton 2011, Valent 2007
N/A; Vitamin C decreases histamine levels by accelerated degradation and by interfering with production Unknown targets to deter mast cell degranulation  Mast cell mediator release regulates many physiologic functions, including allergy response, immune defense against pathogens, angiogenesis, and tissue remodeling. In theory, all symptoms derived from mast cell mediator release. Research has demonstrated decreased release of mediators including histamine and eicosanoids. Molderings 2016
H1 antihistamine; mast cell stabilizer Histamine H1 receptor and mast cell stabilizer (ketotifen) See above for function of targets for H1 antihistamines and mast cell stabilizer See above for symptoms targets for H1 antihistamines and mast cell stabilizer Molderings 2016

 

Table 3: Secondary options for mast cell mediator symptoms or release described in literature
Symptom Treatment Reference
Abdominal cramping H2 antihistamines, cromolyn, proton pump inhibitors, leukotriene antagonists, ketotifen Picard 2013
Abdominal cramping H1 antihistamines, H2 histamines, oral cromolyn, leukotriene receptor antagonists, short course glucocorticoids Valent 2007
Abdominal pain H1 antihistamines, H2 histamines, oral cromolyn, leukotriene receptor antagonists, short course glucocorticoids Valent 2007
Angioedema H1 antihistamines, H2 antihistamines, leukotriene receptor antagonists, aspirin, ketotifen Picard 2013
Angioedema Medications used for hereditary angioedema, including antifibrinolytic such as tranexamic acid, bradykinin receptor antagonist Molderings 2016
Blistering Local H1 antihistamines, H1 antihistamines, H2 antihistamines, systemic glucocorticoids, topical cromolyn, dressing Valent 2007
Bone pain Analgesics, NSAIDS, opiates and radiation if severe Valent 2007
Bone pain Bisphosphonates, vitamin D, calcium, anti-RANKL therapy Molderings 2016
Colitis Corticosteroids active in GI tract or systemic Molderings 2016
Conjunctival injection H1 antihistamines, topical H1 antihistamines, topical corticosteroids, topical cromolyn Picard 2013
Conjunctivitis Preservative free eye drops with H1 antihistamine, cromolyn, ketotifen or glucocorticoid Molderings 2016
Dermatographism H1 antihistamines, H2 antihistamines, leukotriene receptor antagonists, aspirin, ketotifen Picard 2013
Diarrhea H1 antihistamines, H2 histamines, oral cromolyn, leukotriene receptor antagonists, short course glucocorticoids Valent 2007
Diarrhea H2 antihistamines, cromolyn, proton pump inhibitors, leukotriene antagonists, ketotifen Picard 2013
Diarrhea Bile acid sequestrants, nystatin, leukotriene receptor antagonists, 5-HT3 receptor inhibitors, aspirin Molderings 2016
Flushing H1 antihistamines, leukotriene receptor antagonists, H2 antihistamines, glucocorticoids, topical cromolyn Valent 2007
Flushing H1 antihistamines, H2 antihistamines, leukotriene receptor antagonists, aspirin, ketotifen Picard 2013
Gastric symptoms Proton pump inhibitors Molderings 2016
Headaches H1 antihistamines, H2 histamines, oral cromolyn Valent 2007
Headaches, poor concentration and memory, brain fog H1 antihistamines, H2 antihistamines, cromolyn, ketotifen Picard 2013
Interstitial cystitis Pentosan, amphetamines Molderings 2016
Joint pain COX-2 inhibitors Molderings 2016
Mastocytoma (if symptomatic, growing) Local immunosuppressants, PUVA, removal Valent 2007
Miscellaneous/ overall elevated symptom profile Disease modifying anti-rheumatoid drugs, antineoplastic drugs, kinase inhibitors with appropriate target, anti-IgE, continuous antihistamine infusion Molderings 2016
Nasal pruritis H1 antihistamines, topical H1 antihistamines, topical corticosteroids, topical cromolyn Picard 2013
Nasal stuffiness H1 antihistamines, topical H1 antihistamines, topical corticosteroids, topical cromolyn Picard 2013
Nausea H2 antihistamines, cromolyn, proton pump inhibitors, leukotriene antagonists, ketotifen Picard 2013
Nausea H1 antihistamines, H2 histamines, oral cromolyn, leukotriene receptor antagonists, short course glucocorticoids Valent 2007
Nausea Dimenhydrinate, benzodiazepines, 5-HT3 inhibitors, NK1 antagonists Molderings 2016
Neuropathic pain, paresthesia Alpha lipoic acid Molderings 2016
Non-cardiac chest pain H2 antihistamines, proton pump inhibitors Molderings 2016
Osteopenia, osteoporosis Bisphosphonates, vitamin D, calcium, anti-RANKL therapy Molderings 2016
Peptic ulceration/bleeding H2 antihistamines, proton pump inhibitors, blood products as needed Valent 2007
Pre-syncope/syncope H1 antihistamines, H2 antihistamines, corticosteroids, anti-IgE Picard 2013
Pruritis H1 antihistamines, H2 antihistamines, topical cromolyn, PUVA treatment, leukotriene receptor antagonists, glucocorticoids Valent 2007
Pruritis H1 antihistamines, H2 antihistamines, leukotriene receptor antagonists, aspirin, ketotifen Picard 2013
Pruritis Topical cromolyn, topical palmitoylethanolamine containing preparations Molderings 2016
Recurrent hypotension H1 antihistamines, H2 antihistamines, systemic glucocorticoids, aspirin Valent 2007
Respiratory symptoms Leukotriene receptor antagonists, 5-lipoxygenase inhibitors, short-acting β-sympathomimetic Molderings 2016
Severe osteopenia or osteoporosis Oral bisphosphonates, IV bisphosphonates, interferon alpha Valent 2007
Tachycardia H1 antihistamines, H2 antihistamines, systemic glucocorticoids, aspirin Valent 2007
Tachycardia H1 antihistamines, H2 antihistamines, corticosteroids, anti-IgE Picard 2013
Tachycardia AT1 receptor antagonists, agents that target funny current Molderings 2016
Throat swelling H1 antihistamines, H2 antihistamines, leukotriene antagonists, corticosteroids, anti-IgE Picard 2013
Urticaria H1 antihistamines, H2 antihistamines, leukotriene receptor antagonists, aspirin, ketotifen Picard 2013
Vomiting H1 antihistamines, H2 histamines, oral cromolyn, leukotriene receptor antagonists, short course glucocorticoids Valent 2007
Vomiting H2 antihistamines, cromolyn, proton pump inhibitors, leukotriene antagonists, ketotifen Picard 2013
Wheezing H1 antihistamines, H2 antihistamines, leukotriene antagonists, corticosteroids, anti-IgE Picard 2013

 

[i] Valent P, et al. (2007). Standards and standardization in mastocytosis: Consensus statements on diagnostics, treatment recommendations and response criteria. European Journal of Clinical Investigation, 37(6):435-453.

[ii] Picard M, et al. (2013). Expanding spectrum of mast cell activation disorders: Monoclonal and idiopathic mast cell activation syndromes. Clinical Therapeutics, 35(5):548-562.

[iii] Molderings GJ, et al. (2016). Pharmacological treatment options for mast cell activation disease. Naunyn-Schmiedeberg’s Arch Pharmol, 389:671.

[iv] Hamilton MJ, et al. (2011). Mast cel activation syndrome: a newly recognized disorder with systemic clinical manifestations. Journal of Allergy and Clinical Immunology, 128(1):147-152.e2

The currency of suffering

I have always been fascinated by medicine. I have very early memories of playing with a Fisher Price medical kit with a doctor’s bag and facsimiles of instruments in faded plastic. I had an assortment of “medical books” as a kid, including part 2 of a medical dictionary published in 1993 that covered I-Z. If your condition was in A-H, it was out of my hands.

As strange as this sounds, one of the things I have always appreciated about medicine is the lack of aesthetic sanitation. Medicine shows things as they really are. Not practitioners, not doctors or reports – that’s different. But medicine in the purest sense is inherently graphic, unencumbered biology. It is blood and cells and inflammation and organs, physiology that works around defects structural or functional. There is no pretense. Medicine is gross.

Over the course of my life, I have seen medicine become more visible, more mainstream, better accepted and better understood by society. Initially, the stories about medicine consumed by the public were sanitized. A lot of pain, a lot of consequences, very little blood, puke and stool. Bald heads but not packed wounds, darkened loose skin but not skin taut and stretching to contain the liters of edema beneath it. Society mostly endorsed the idea of being sick without the putrid physical evidence of it.

But then Al Gore put all those tubes together and the internet became a thing. Online articles and email became a thing. Then blogging and social media. Personal revelation became more prized and lauded and the demand for new material was large. This intense interest in revelation and soul searching skewed favor towards people who had a renewable resource of emotionally trying things to reveal. We became invested in the daily lives of these people. A lot of those people were sick.

There is a fetishism about sickness that can be deeply trying. The interest is not just about the illness and how we live with it. It is about the attitude and the perseverance. People think there is an honorable way to deal with illness that is almost transcendent. There are two diverging paths stemming from a single point: the desire for deep, graphic revelation in tandem with the exclusive public expression of hope and lessons learned. There is a currency in suffering.

I am generally optimistic and hopeful. It is my preferred coping mechanism and is genuinely how I perceive the world and myself in it. I am also a deeply analytical and pragmatic person. It is sometimes difficult for people to reconcile the fact that I am hopeful about the future while simultaneously being very realistic and raw about my life.

I am recently having a hard time with the expectation that I should police my speech when talking to others about my health. If I’m honest, it’s less a hard time and more something that enrages me. It’s not okay that sick people are so often put into positions where they are expected to comfort others about the fact they are sick. It’s not okay that by talking frankly about complications of my disease and how sick I am of puking up everything I eat and how it takes me six hours to get stool out of my body, I am accused of being negative.

I believe the world is still a good place and that things will get better but let’s be real. Believing those things is not going to prevent me from having anaphylaxis or a bowel obstruction or gastroparesis. It is not going to make my GI tract move. It is not going to stabilize my blood pressure.

The difference in reaction to serious health news is vastly different among people who are chronically ill and those who are not. And it’s not really talked about because so often, we care a lot about these people who are trying to change the narrative of our stories. The difference is stark. Last week, a dear friend who is also chronically ill asked if I had a current will that had details of who I wanted to care for my animals if I pass. (I do). Shortly after, while talking to a very well intentioned person, I was repeatedly shushed and talked over with such phrases as “God forbid” and “You can’t give up like that” and “That’s giving up” and “You just have to fight”.

Every second of every day is a fight. A gross fight. A fight with blood and shit and needles and so much puke. A fight when your head feels like it is being crushed and you need to not puke to keep down your oral meds and you are in bed 18 hours a day. A fight that generates an unbelievable amount of trash in piles on every countertop and table, flush wrappers and syringe caps, used alcohol swabs, and sharp containers filled to the brim. A fight to remember which pharmacy I have to call today and what I have to get approved by insurance and what appointments I have and which I need to schedule and what meds need to be filled. I fight, even if people think me being frank is giving up. Every second, I fight.

I am real. My diseases are real. The mess and the garbage and the grossness are real. The expectations and the danger of being this sick are real. None of this is internet magic. My port is real, the constantly getting my lines tangled is real, the screaming into a towel while trying to stool is real. My scars from my ostomy, from my PICC line, from my other surgeries, are all real. The voids inside me where pieces have been taken out of me are all real. The planning for a future in which I can’t work or will succumb to this disease sooner than later is all real. The taking medication every thirty minutes while I’m awake is real.

Pretending that my health does not present a tangible risk to my life is just absurd. I can no longer live in a space where people think that thinking positive will save my life, overcome my need to IV meds, overcome my inability to eat, overcome my inability to get waste out of my body. This shit is real. I need every available piece of energy to fight, especially the fights people can’t see.

I am positive when I feel positive and I am not when I don’t. I am happy and mad and sad and numb when I feel happy and mad and sad and numb. I am realistic and pragmatic when I need to be. All of these parts of me are real and they are all part of this fight.

It is not my job to make people feel better about the fact that I am sick. It is my job to stay alive.

In bed

A wicked symmetry

The GI tract moves. You chew food and swallow it but after that, the tract is on its own. Smooth muscle contracts and relaxes in rhythm, marking time by the forward propulsion of what you consumed. The food is pushed down the esophagus in a matter of seconds before entering the stomach. The GI tract moves. Hormones and enzymes and acid are released in the stomach. Digestion begins. The GI tract moves. This partially digested product is pushed through the pyloric valve into the small intestine. The GI tract moves. The food is degraded and all of its useful parts liberated. They are shuttled out of the intestine to nourish the body. The GI tract moves. The remaining substance is pushed to the colon. The colon reabsorbs water and minerals. The GI tract moves. Devoid of any nutritional role, the stool is passed through the rectum and the anus, where it leaves the bottom. Meters of GI tract. It all moves.

There is a line when you have serious GI motility issues. The issues are serious on either side of the line but we become defined by the choice to step across it. It changes everything and you can never go back.

This is the line: when you are afraid to put food into your body because you don’t know if you can get it out.

To say that my GI tract doesn’t move properly is laughably understated. It is so hard for me to get stool out of my body that I had an ostomy for years and will probably have an ostomy again. I currently rely on the magic of lidocaine gel, glycerin suppositories, and disimpaction to stool. The colon is the hill my GI motility has chosen to die upon. Above that, I have trouble, but it hasn’t been appreciably from dysmotility. I puke a lot and sometimes there’s blood in there and I need multiple doses of multiple meds daily to manage my nausea, but that was never from upper GI dysmotility.

Except this week, after several weeks of bad epigastric pain with eating on top of my abdominal neuropathy, colitis, and rectal pain, I am now vomiting up mast cell safe meals hours after eating it, completely undigested. My stomach is not moving food into the small intestine and it’s not digesting it either.

There is almost nothing I can do to my diet to improve GI motility beyond not eating solids. I can’t add in foods that are known to help because I either have serious mast cell reactions to them or they are contraindicated in colitis patients. Anything with fiber is dicey if I’m having colitis and I basically have colitis all the time. Up to this point, I have been able to minimize gastric pain as long as I ate foods I didn’t react to and that weren’t colitis triggers.

That is no longer the case. My stomach won’t do it anymore. It just won’t move food and it won’t break it down. Whatever does get below the stomach, mostly by gravity, eventually arrives at the colon and we all know how well that goes. I can’t keep food in my upper GI tract and can’t get it out of my lower GI tract, a sort of wicked symmetry.

The GI tract is composed of related but dissimilar parts. They are only really related because they are connected. The small intestine and the stomach and the rectum don’t have a ton in common if you remove this fact. Their allegiance is real but fragile. It is not that hard to break it.

For reasons that are hotly debated (including mast cell degranulation, nerve damage, and microbiome disruption), the GI tract stops working when you touch it. Post operative ileus is the most classic example of this phenomenon. Usually, the tract starts working again. But there is a limit. There is a limit to how many times you can touch the GI tract before it just stops working.

The continuity of my GI tract has been altered, sections removed and non-contiguous pieces sutured together. I have had scopes via all three access points to my GI tract, so many of them, and so many biopsies. All these little pieces torn out of me with cold forceps, these little pieces fixed in formalin. These little pieces that leave little craters, until the topography of my GI tract is as foreign as the surface of the moon. A moon that doesn’t even recognize itself and can only appreciate a wicked symmetry.