THALIA HALE, ND

Mast Cell Activation (MCA) is demanding awareness in functional medicine practices, especially among practitioners working with patients with chronic complex illnesses and infections such as chronic dysbiosis, Sick Building Syndrome, and Lyme disease and its associated infections.

MCA patients may appear complex in nature, as the syndrome affects multiple systems in the body; this can result in an array of seemingly unrelated symptoms. Fortunately, as naturopathic doctors we have a foundational understanding that the body is wholly connected.

The Role of Mast Cells in the Body

Mast cells (MCs) are a subset of our white blood cells derived from bone marrow. Upon leaving the bone marrow, MCs become a part of our body’s first line of defense. The highest concentrations of these cells are found in the skin, epithelial lining of the lungs, nasal passage, conjunctiva, and digestive tract. This positioning is key, as they predominate in the areas where our cells come into contact with the outside world.

If a harmful substance enters our environment, it is perceived as dangerous when the antigen attaches to the mast cell. This causes the basophilic granules within the mast cell to release histamine, heparin, inflammatory cytokines, and other mediators into the extracellular environment. The physiologic effects of histamine release by MCs include vasodilation, increased capillary permeability, bronchoconstriction, and smooth muscle contraction.¹

Since first studied by Paul Ehrlich in 1878, MCs have primarily been considered part of our innate immune response and mostly involved in allergic and anaphylactic responses. But in the last 3 decades, further studies have revealed that our knowledge of these cells has been limited.¹

Our MCs play a part in adaptive immunity by recognizing invaders such as viruses, fungi, parasites, and bacteria. They interact with a number of other immune cells to potentiate physiologic and immunologic responses to environmental changes.¹

When MCs respond appropriately, they are immunomodulatory and support tissue healing, vascular homeostasis, angiogenesis, bone and tissue remodeling, and immune tolerance.¹ When in a maladaptive state, however, MCs can inhibit Th1 immunity and shift a greater emphasis to Th2 immunity, resulting in patients feeling allergic, inflamed, and unable to respond adequately to chronic infections.

Mast Cell Activation

Overstimulation of MCs, which leads to a large release of histamine and inflammatory mediators, has been shown to contribute to chronic allergic/inflammatory disorders, autoimmune diseases, cardiovascular disease, and cancer.¹Dermatologic findings can be merely 1 clue to underlying immune and inflammatory dysregulation. This overstimulation of MCs can result in multi-systemic symptoms, including those listed in Table 1 (those accompanied by an asterisk are the most common manifestations of MCA that I see in practice).

Table 1. Manifestations of Mast Cell Activation

Dermatologic Manifestations: Angioedema Dermatographia Dermatitis with pruritis Erythema Generalized pruritis* Hives* Hypersensitivity to insect bites* Skin flushing Sun sensitivity	Gastrointestinal Manifestations: Abdominal bloating* Abdominal cramping Constipation Diarrhea* Gastroesophageal reflux* Peptic ulcer disease Sensitivity to probiotics

Musculoskeletal Manifestations: Arthralgias Myalgias Osteoporosis	Cardiac/Pulmonary Manifestations: Heart palpitations* Hypotensive syncope/Near-syncope* Tachycardia Wheezing

Ear/Eyes/Nose/Throat Manifestations: Conjunctival injection Rhinitis, especially after meals* Sinus congestion	Endocrinologic Manifestations: Blood sugar instability* Fatigue Orthostatic hypotension*

Brain/Neurological Manifestations: Anxiety* Cognitive deficit/Brain fog Headaches*	Urinary Manifestations: Dysuria Polyuria*

MCA has a number of comorbidities, including:

Ehlers-Danlos Syndrome (EDS)²
Electrohypersensitivity^3,4
Irritable Bowel Syndrome (IBS)⁵
Inflammatory intestinal disorders⁵
Periodontal disease⁶
Postural Orthostatic Tachycardia Syndrome (POTS)²
Sick Building Syndrome^7-9
Small Intestinal Bacterial Overgrowth (SIBO)¹⁰

The severity of symptoms depends on a number of factors, including the number of MCs involved in the reaction; the amount and type of allergen-specific IgE; the triggering allergen; the presence of triggering cofactors such as exercise, alcohol, or acetylsalicylic acid (aspirin); the presence of comorbidities; the tissue microenvironment; and the cytokines/chemokines involved.¹¹

If your patient is complaining of many of the symptoms and conditions listed in Table 1, it is important to take MCA into account as a potential contributing diagnosis. There are 2 subclasses of Mast Cell Activation Syndrome (MCAS): primary (clonal) and secondary (nonclonal). For the purposes of this article, I will be focusing on secondary MCAS, which encompasses IgE-mediated, direct, and idiopathic MCA.¹²

Work-Up for MCAS

The likelihood of MCA being present is high when you 2 or more of the Table-1 symptoms are present and your patient is responsive to drugs that block MC mediator effects, mediator production, and/or mediator release.

The current minimal diagnostic criteria for MCAS, as of November 2020, are as follows¹¹:

Typical clinical symptoms indicative of multi-organ involvement, usually meeting the criteria for anaphylaxis

Serum tryptase greater than 1.2 x baseline value + 2 ng/mL during a flare of symptoms is considered indicative of MCA and/or a clear increase in another mast cell-mediated marker

Responsiveness to medications that manage MCA, mast cell mediator release, and/or mast cell mediator effects

Elevations in serum histamine and/or serum tryptase strongly support the diagnosis and the ability to use the marker(s) as a therapeutic guide. The challenge faced with random testing of serum histamine and tryptase is that these markers are extremely transient; thus, a normal value cannot rule out MCA.

Managing & Monitoring MCA

In our office, we focus on chronic diseases like Sick Building Syndrome and chronic infections like Lyme disease and its coinfections, gut dysbiosis, chronic viruses, and parasitosis. About 80% of our patients have some degree of MCA symptoms and often do not have elevated tryptase levels. Most of these patients have a number of associated symptoms (often without anaphylaxis) and elevated inflammatory markers and respond positively to mast cell treatment.

Treatment of MCA can be intense, as it most often requires strict dietary management and other lifestyle interventions in addition to pharmaceutical/nutraceutical interventions. In order to objectively assess the patient’s condition and help guide management and treatment of MCA, we have found the inflammatory marker Matrix Metaloproteinase-9 (MMP-9) to be very helpful.

MMP-9 is a key effector in immediate-type allergic reactions and is also well known to contribute to the pathogenesis of a variety of non-allergic inflammatory responses. This extracellular matrix-destructive enzyme is involved in tissue remodeling, embryonic development, wound healing, angiogenesis, and more. When improperly unleashed by mast cells, this enzyme sets up a cascade of inflammatory cytokines and chemokines (see Table 2 for interpretation of levels).^13-15

Table 2. MMP-9 Interpretation

MMP-9 Level (ng/mL)	Interpretation
0-983	Normal reference range
< 250	Normal; mast cell activation unlikely
250-399	Consider mold and/or mast cell activation
>400	Mast cell activation highly likely

In an in-office study, we obtained MMP-9 values from 22 of our patients before and after a 3-4-week low-histamine diet and no MC stabilizers. After the diet trial alone, we observed a 39% decrease in MMP-9 levels. In addition, patients reported symptomatic improvement, including reductions in anxiety, fatigue, arthralgias, headaches, congestion, abdominal pain, loose stools, reflux, pruritis, and more.

Inflammatory markers can be elevated by numerous conditions, but being able to objectively show patients their progress has been imperative for treatment compliance.

Triggers for MCA

Whether based on symptoms and empiric treatment and/or lab work-up, one of the greatest challenges in treating patients with MCA is identifying and appropriately treating the triggers for their condition. As mentioned briefly above, pathogens and/or any harmful substances can trigger mast cells to become overstimulated.

Triggers to take into consideration include, but are not limited to, the following:

Mold/Mycotoxins^7-9
Electromagnetic frequency (EMF) exposure^3,4
Impaired detoxification
Methylation
Glucuronidation
Heavy metal exposure¹⁶
Chemical/Pesticide exposure¹⁷
Estrogen dominance¹⁸
Viruses and retroviruses¹⁹
Fungal infections²⁰
Parasitic infections^19,21,22
Bacterial infections^19,20
Dysbiosis via viruses/fungi/bacteria/parasites
Mycoplasma pneumoniae
Chlamydia pneumoniae
Lyme disease and its associated infections
Streptococcus species
Emotional stress/Trauma²³
Limbic system impairment
Vagus nerve impairment

Treatment for MCA

Dietary Interventions

Our office has observed that dietary intervention is the first step in managing patients with MCA. It is imperative for these patients to limit their exposure to additional histamine and triggers during the course of treatment.

There are 2 major rules for a low-histamine diet:

Avoid high-histamine foods, including fermented foods
Avoid leftovers

Leftovers and fermented foods allow naturally occurring bacteria to break down amino acids into histamine. Once histamine has been created within food, it can no longer be destroyed. We thus recommend that patients prepare their food immediately upon purchasing, and to freeze any leftovers for later consumption. Even food sitting in the refrigerator is susceptible to degradation.

Helpful guides are available, such as the “All I Can Eat” phone application, which may help people understand histamine levels in foods.

Other potential food triggers to consider include oxalates, lectins, and salicylates. For obvious reasons, most patients do not do well on a combination of more than 2 restricted diets, as it can become overwhelming, both mentally and physically. Patients limited to only a few tolerated foods often have other triggers that require attention, like limbic system and/or vagus nerve impairment, or mold.

Environmental/Lifestyle Interventions

As mentioned above, it is critically important to explore the triggers of a patient’s MCA and to address them in the necessary order. Outside of dietary intervention, various environmental and lifestyle factors may support a patient’s healing process:

Reduction of EMFs^3,4
Inclusion of mindfulness, meditation, limbic system/vagus nerve support²²
Reduction of exposure to water-damaged buildings^7-9
Transitioning to organic foods¹⁷
Addressing sources of heavy metals¹⁶

Pharmaceutical & Nutraceutical Interventions

Once we have addressed dietary, environmental, and lifestyle influences on one’s presentation of MCA, we then introduce pharmaceutical and/or nutraceutical support to further stabilize their condition. By focusing on the foundational components early on, we find that we need fewer MC stabilizers and can use lower doses effectively for management. Most of our patients are on 3-4 MC-stabilizing agents, including probiotic strains that reduce histamine levels.

Pharmaceuticals

Pharmaceuticals used in the management of MCA include¹⁸:

1^st Generation H1 Anti-histamines
Chlorpheniramine – mildly sedative: 1 daily with food
Diphenhydramine – highly sedative: 1 daily if needed
2^nd Generation H1 Anti-histamines
Decreased central effects, resulting in less sedation
Fexofenadine: 1 daily with food
Loratadine: 1 daily with food
Cetirizine: 1 daily with food
Levocetirizine dihydrochloride: 1 daily with food
Other Anti-histamine Support
Selective H1 receptor inhibitor/Mast cell stabilizer – Ketotifen 1 mg (compounded): 1 daily with food
Mast cell stabilizer – Cromolyn sodium (prescription/compounded): 100-200 mg 2-3 times daily, 5-10 minutes before meals
H2 Anti-histamines (Rarely used in our practice due to long-term GI effects)
Ranitidine
Cimetidine
Famotidine

Nutraceuticals

Nutraceuticals used in the management of MCA include:

Quercetin, 250 mg: 2-3 times daily with food²⁴
Luteolin, 100 mg: 2-3 times daily with food^25,26
Curcumin, 200 mg: 1-2 times daily with food^27,28
Holy basil, 200-300 mg: 1-2 times daily with food²⁹
Pantethine, 450 mg: 1 twice weekly to every other day, with food³⁰
Fisetin: 1 cap 2 times daily³¹
DAO, 600 µg: 2-3 times daily, 10-15 minutes before meals
Homeopathic preparations of histamine: 1-3 drops 1-3 times daily, sublingually

Probiotics

Similar to SIBO patients, patients with MCA may have worsening symptoms when taking probiotics, and thus need specific strains to avoid aggravating histamine levels.

Probiotic strains to avoid in MCA:

Lactobacillus bulgaricus

Lactobacillus casei

Lactobacillus reuteri

Streptococcus thermophilus

Histamine-neutral strains:

Lactobacillus acidophilus

Lactobacillus lactis

Lactococcus lactis

Probiotic strains supportive of MCA:

Soil-based probiotics

Bifidobacterium infantis

Bifidobacterium longum

Lactobacillus gasseri

Lactobacillus rhamnosus

Lactobacillus plantarum

Lactobacillus salivarius

Summary

The unfortunate truth is that our environment has become increasingly toxic. Because mast cell activation can impact so many different organ systems and functions, the assessment and treatment of MCA has become a cornerstone in our treatment of chronic and complex patients. By reducing immune and inflammatory overexpression via specific dietary and lifestyle interventions, identification of MCA triggers, and the use of targeted nutraceuticals and probiotics, we are able to adequately address MCA and restore optimal health in our patients.

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Thalia Hale, ND is a naturopathic doctor in the San Francisco Bay Area. Dr Hale has been practicing 10 years. Treating chronic digestive and hormonal conditions led her to specialize in chronic complex patients presenting with mast cell activation, mold-related illness, and Lyme disease and its coinfections.