The body’s defense against any stressor begins with the hypothalamic-pituitary-adrenal (HPA) hormonal axis. This term collectively refers to signals regulating what these glands do. This includes the hypothalamus, the pituitary gland, and the two adrenal glands

1. MAST CELL ACTIVATION SYNDROME:
THE IMMUNE SYSTEM GONE WRONG –
PART 2
The Role of Stress on Mast Cell Activation
Stress, whether the source is physiological, psychological, or environmental in nature, directly impacts
the neuroendocrine system and mast cell activation components.
The body’s defense against any stressor begins with the hypothalamic-pituitary-adrenal (HPA) hormonal
axis. This term collectively refers to signals regulating what these glands do. This includes the
hypothalamus, the pituitary gland, and the two adrenal glands (each situated on top of a kidney). The
HPA axis, besides handling stress, also plays a role in digestion, metabolism, sexuality, emotions, and
immune functions.
The job of the hypothalamus, which is situated in the brain, is to regulate metabolism and release
neurohormones. It also assists with hunger, thirst, sleep, energy levels, body temperature, and circadian
rhythm.
The pituitary gland also releases a number of hormones. Amongst these are a thyroid stimulating
hormone, human growth hormone, and a number of others. They are released when the hypothalamus
sends chemical signals to the pituitary gland.
The adrenal glands, in their turn, synthesize and release corticosteroids, such as cortisol and
catecholamines, such as norepinephrine and epinephrine, in response to messages received from the
pituitary gland. They are also responsible for the manufacture of androgens (sex hormones) and
aldosterone, which helps blood pressure regulation.
When under stress, the hypothalamus releases chemical messengers, known as corticotropin-releasing
hormone (CRH), that stimulate the pituitary gland to release adrenocorticotropic hormone (ACTH),
which then stimulates the adrenal glands to produce and secrete cortisol.
In turn, the heightened cortisol production sends stimuli to the hypothalamus and pituitary gland to
slow down their hormone production. Usually, once the stressful situation has passed, the body returns
to normal, and all hormone production resumes at its usual pace.
When stress continues for prolonged periods, however, the hypothalamus produces an increasing
amount of CRH, which in turn leads to an increase in cortisol production. If this continues for too long,
adrenal fatigue and its accompanying symptoms are usually the results.
Additionally, CRH binds to receptors on mast cells and stimulates the release of certain contents.

2. Histamine can be a stressor that triggers this process.
Cortisol and the Histamine Reaction
Whereas histamine causes inflammation, cortisol is anti-inflammatory. Thus, your body releases extra
cortisol as a response to the inflammation caused by the histamine. This puts a strain on your adrenal
glands because they have to manufacture ever-increasing amounts of cortisol to counteract the
histamine.
If the situation continues for too long and Adrenal Fatigue Treatment sets in, especially in the advanced
stages, the body’s cortisol production can no longer keep up with demand and production decreases.
The end result is a state of inflammation with a number of diverse symptoms:
 Headaches
 Coughing
 Bloating
 Stomach pain
 Congestion
 Allergies
 Sensitivity to certain foods
 Heat intolerance
 A runny nose
The Cortisol, IBS, and MCAS Connection
Using the NeuroEndoMetabolic (NEM) Stress Response paradigm, much of the inflammation in the body
stems from the immune system, digestive system, and microbiome. Inflammation of the gut can present
as Irritable Bowel Syndrome (IBS or leaky gut). Interestingly, those with IBS also show a marked increase
in histamine secretion from their mast cells, indicating a strong correlation between IBS and Mast Cell
Activation Syndrome. The higher the histamine concentration, the worse the symptoms seem to be.
Mast cells, as you know, are part of the immune system. Thus there is a connection between the
immune system and the digestive system, both of which are integral to the inflammation circuit.
Because of the increase in inflammation, there is also initially an increase in cortisol, which results in the
suppression of the immune system. This leads to inhibited digestion and suppresses the good bacteria in
the gut, causing IBS or exacerbating it.
In the latter stages of adrenal fatigue, there is a progressive decline in the production of cortisol, as the
adrenals can no longer keep up the supply demanded by the body to counteract the effects of the
histamine reaction in the gut. This, in turn, leads to an increase in gut inflammation and a dysregulation
between good and bad gut bacteria, which worsens IBS.

3. The symptoms of this condition include:
 Abdominal pain
 Cramping
 Bloating
 Diarrhea and constipation (either one or alternating)
 Weight loss
Identifying Mast Cell Activation Syndrome
The symptoms of MCAS overlap with many of the disorders belonging to this family. Sufferers may
present only a few symptoms or many. No two sufferers necessarily present the same symptoms. It
depends on the person.
Common MCAS symptoms include:
 Hives
 Rashes (which may or may not itch)
 Pruritus (itching with or without a rash)
 Irritable bowel syndrome with either diarrhea or constipation (or alternately)
 Gastrointestinal problems, including pain, bloating, reflux, and gas
 Extremely dry skin that can be ‘written’ on (dermatographia)
 Reactions to certain local or general anesthetics (hives, vomiting, stomach pain, or diarrhea)
 Allergies or sensitivities to certain foods and drugs
 Alcohol sensitivity
 Anaphylaxis from dyes, bee and wasp stings

4.  Esophageal spasms (finding it difficult to breathe)
 Difficulty breathing (sneezing, coughing)
 Headaches
 Brain fog, irritability, dizziness
 Formation of reddish/brown spots (urticaria pigmentosa)
 Angioedema (swelling of the eye and lip area)
 Flushing in the face and neck due to food, heat, or stress
 Bone issues (bone loss, osteosclerosis, osteoporosis, and osteopenia)
 Frequent waking at night
Although someone with Adrenal Fatigue Syndrome does not necessarily have MCAS, someone with
MCAS has many symptoms of adrenal fatigue.
Fortunately, mast cell activation is something that can be tested for in order to determine whether you
have it. With many ailments in this family, conclusions are arrived at by a process of deduction. In the
case of MCAS, however, while the medical establishment might initially misidentify the condition, you
can ask for testing if you feel it might be the source of your issues.
Eliminating other Possibilities
A systematic approach is suggested for identifying this condition. This includes making sure you meet all
the criteria to be considered for it. You also need to have two to three symptoms relating to the organs
that suggest the activation of mast cells, such as diarrhea, wheezing, flushing, or urticaria.
Before considering MCAS, the possibility of conditions such as IBS, medullary thyroid cancer, POTS,
pheochromocytoma, estrogen or testosterone deficiency, reactions to possible environmental toxins,
autoimmune conditions, and allergies all must first be eliminated.
Testing for MCAS
N-methylhistamine 24-hour urine test
This test measures the levels of your histamine, prostaglandins, and leukotrienes. If high levels are
present, further testing can be conducted to rule out mastocytosis. Unlike MCAS, those with
mastocytosis have elevated levels of white blood cells.
Serum Tryptase Test
Tryptase is a marker showing the amount of degranulation that has taken place in mast cells. Tryptase
levels that are over the normal count but under 20 ng/ml indicate the possibility of Mast cell activation.
When over 20 ng/ml, it indicates the probability of systemic mastocytosis.
A Complete Blood Count
It needs to be comprehensive, including serum magnesium levels.

5. Bone Marrow Biopsy
A bone marrow biopsy can indicate the presence of mastocytosis. If the biopsy is negative, it effectively
eliminates this similar condition and indicates the possibility of MCAS.
MCAS Testing Considerations
In many instances, when someone has MCAS the tryptase and histamine levels present themselves as
normal, so these tests often need to be done twice: once at baseline, and once when you are
manifesting symptoms of the condition.
Generally speaking, someone with anaphylaxis could conceivably have MCAS, although not everyone
with MCAS necessarily has anaphylaxis.
In cases where one proves positive on tests and there are no clinical markers present, an MCAS
diagnosis may still be considered.
Managing Mast Cell Activation Syndrome
In conventional medicine, the symptoms of MCAS are often addressed, but the source is not identified.
In many cases, people only discover MCAS years after the condition presents itself. Most methods of
managing the syndrome include H1 and H2 antihistamines, or their generic counterparts, along with
mast cell stabilizers, such as cromolyn sodium and ketotifen.
Antihistamines
The difference between H1 and H2 antihistamines is primarily their area of action:
H1 antihistamines work on H1 histamine receptors such as those found on smooth muscle cells
throughout the body. These antihistamines are those that are often bought over the counter or
recommended by doctors.
H2 histamines work on H2 histamine receptors. H2 histamine receptors bind with histamine in the same
way as H1 histamine receptors, except that they are found in the stomach lining. When these receptors
are stimulated, they cause some symptoms related to MCAS to manifest, such as indigestion, an
increase in stomach acid production, and other associated issues. These antihistamines are also
available over the counter or via your doctor.

6. The Pros of Using Antihistamines
 They are very effective at addressing the symptoms.
 They are easily available.
 They are fast working.
The Cons of Using Antihistamines
 They address the symptoms, not the root cause of the problem.
 Long-term use is usually needed for controlling symptoms.
 They usually have certain side-effects, possibly including drowsiness and dry sinuses that are
prone to infections.
 They may suppress the immune system, making you predisposed to infections.
 They may have a negative action on your adrenal glands.
 They may constrict blood vessels, decreasing blood flow to certain areas of the body and raising
your blood pressure.
 They may interfere with your sleep patterns.
 They could lead to oxidative stress.
As with most medications, the use of antihistamines in cases of MCAS should be judicious and not
undertaken without consulting a healthcare professional.
Cromolyn Sodium
Cromolyn Sodium is an anti-inflammatory medication. As such, it prevents the body from releasing
inflammation-causing substances such as histamine. Cromolyn sodium is commonly used by asthmatics
to prevent bronchospasms typically brought on by pollutants, exercise, or air-born chemicals. It is also
commonly used to manage MCAS.

7. The Pros of Cromolyn Sodium
 It is preventative in nature and decreases your chances of having an asthma attack.
 It prevents the release of histamines in the body.
 It has an anti-inflammatory action.
The Cons of Cromolyn Sodium
 Some people have an allergic reaction to this medication.
 It does not stop an asthma attack in progress.
 It needs to be used regularly in order to be effective.
 It is not to be used by those with a history of heart disease, liver disease, kidney disease, or
coronary artery disease unless certain precautions are taken.
If you have any of the above-mentioned conditions, make sure to mention them to your healthcare
professional as incorrect dosage could have dire results.
Ketotifen
Ketotifen is a noncompetitive H1-antihistamine and mast cell stabilizer. It is only available through your
doctor, and it reduces the severity of asthma and other bronchial manifestations of MCAS. It works by
inhibiting the release of mast cell activation contents resulting in asthma and inflammation.
The Pros of Ketotifen
 It is a long-term solution.
 It helps prevent the onslaught of histamine attacks.
 It inhibits granulation in mast cells.
The Cons of Ketotifen
 It can cause serious side effects.
 Side effects can include fever, headache, joint pain, sore throat, shivering or chills, trouble
sleeping, sweating, tiredness or lethargy, vomiting, and coughing.
 These side effects can be a sign of other issues, and if you experience them on ketotifen, you
need to contact your health professional right away.
Unfortunately, most medications aimed at managing MCAS are aimed at addressing the various
symptoms while suppressing certain actions in the body. They do not address the root cause of the
problem.
Natural Remedies for Mast Cell Activation
The first step in addressing MCAS from a natural perspective is through diet. This means cutting out
foods that induce a histamine reaction and concentrating on low histamine foods. Foods naturally high
in histamine include pickled and canned foods, smoked meat products, beans and pulses, shellfish,
cocoa-based products, fast foods/junk foods, sugar, and artificial coloring and preservatives.

8. Low histamine foods include the freshest fruit, chicken, meat, and fish. You can also try some fresh
vegetables (not tomatoes), grains (such as rice, oats, spelled and corn-based pasta, and yeast free rice
bread), milk substitutes such as coconut and rice milk, leafy herbs, and some herbal teas (green tea).
Certain supplements also help with the problems surrounding MCAS. They include:
 Curcumin (found in turmeric) is an antihistamine that helps with stabilizing mast cells.
 Garcinia mangostana inhibits the release of histamine and prostaglandin.
 Reservatrol (in grapes and blueberries) suppresses inflammatory cytokines which are linked to
MCAS.
 Ellagic acid (in pomegranate and mango kernels) prevents the release of proinflammatory
agents from mast cells.
 Silibinin (in milk thistle) prevents the release of inflammatory agents in mast cells.
 Theanine (found in green tea) is an amino acid that helps prevent histamine release.
 Epigallocatechin gallate (also found in green tea) inhibits histamine release.
 Quercetin combined with bromelain has antihistamine properties without causing drowsiness.
 Fish oil reduces inflammatory responses.
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