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Mast Cell Activation Disorder (MCAD)

Mast Cell Activation Disorder

Mast cell activation disorder (MCAD), also called mast cell activation syndrome (MCAS), is a condition of aberrant mast cell activity in response to stimuli that normally do not activate mast cells or with excessive mast cell responses.

Mast Cell Biology

Mast cells are cells of the immune system that derive from bone marrow.  Immature cells are released into the blood and travel to different locations throughout the body, directed by different chemicals produced by other immune cells.  When they reach their destinations, they differentiate into their mature forms and remain local; they do not return to general circulation.

Mast cells are found in all tissues except the central nervous system and the retina of the eye, and can be divided into “mucosal” and “connective tissue” types. (1,2)  Mucosal mast cells are found in the lining of the organs and tissues and the connective tissue types are found in high numbers in connective tissues, including tendons, ligaments, cartilage, and fat.

Mast cells store a huge number of different chemicals. The most well-known ones include histamine, interleukins, proteoglycans (e.g., heparin), tryptase, proteases, other enzymes, and cytokines, which are stored in sacs or granules. When the mast cell is stimulated by a trigger, they release the contents of their granules into the surrounding tissues, which produce local responses characteristic of mediator(s) released. (3)  On stimulation, mast cells can also synthesize new chemicals in addition to the pre-formed ones in the granules.  Mast cells can be triggered by allergens causing an IgE antibody reaction with receptors on the surface of the mast cell.  However, mast cells can be affected by triggers other than IgE, and the amount, duration, and rate of the response will depend on the type of trigger. (4)

The chemicals released by mast cells have a wide range of effects.  Histamine is most often associated with allergic responses, but it also causes the release of gastric acid in the stomach, acts as a neurotransmitter in the brain, and a communication chemical for many cells of the immune system. (5) Heparin prevents clot formation and tryptase plays an important role in inflammation.  Proteases are enzymes that break down proteins, which can be important in destroying bacteria or tissue remodeling from wounds.  Cytokines are communication chemicals of the immune system.  Other mast cell chemicals may oppose inflammation or regulate the release of mediators from the granules and can enhance or suppress their actions once released.

Mast cells play an important role in immune function.  They can exert a positive (enhancing) or negative (suppressing) effect on other cells of the immune system, changing the overall immune response.  They serve as a first-line defense and are involved in the development and maturation of T cells. (6) They can help clear bacterial infections, and enhance immune reactions by modulating inflammatory responses to infections. (7)  Mast cells also play a key role in clearing the chemicals produced by the immune system to kill infections, which is important because many of these chemicals can have adverse effects at high concentrations. (7)  Mast cells can also have protective functions against different venoms and parasites and can help prevent sepsis-related mortality associated with infections. (8)  Several of the chemicals released by mast cells can promote blood vessel formation, which is important in wound healing. (9)

Overall, mast cells can have a powerful effect on every system of the body.  These effects can be protective or harmful, depending on the type and amount of the chemicals they release into the surrounding area.

Other Mast Cell Related Conditions

Most commonly, mast cells are associated with allergies because of the histamine release due to the IgE antibody trigger.  With exposure to an allergen, people generally have symptoms in the system that contacted the allergen, i.e., respiratory symptoms from an inhaled allergen, or skin symptoms from a topical exposure.  Exposure to food allergens also most commonly cause gastrointestinal symptoms but can cause more systemic symptoms if the allergen is absorbed into the body through the intestines.

Other conditions associated with mast cells are systemic mastocytosis (SM) and possibly histamine intolerance.  SM differs from MCAD in that SM is a group of disorders characterized by increased actual numbers of mast cells and infiltration of mast cells into the skin, other organs, or both. (10)  SM is caused by a gene (KIT-816V) mutation that allows for uncontrolled proliferation of mast cells.  “This mutation isn’t seen consistently in MCAD but has supported theory that there may be mutations affecting mast cell biology.  A genetic cause is a likely factor because the risk of MCAD in patients with a relative with MCAD is triple that of the general population.” (11)  Dr. Lawrence Afrin, one of the main researchers into MCAD, theorizes that there are “one of more inheritable ‘genetic fragility factors’ which interact with different stressors…to cause additional non-inheritable mutations” (11) and that combination of mutations can lead to MCAD.

Histamine intolerance can cause many similar symptoms to MCAD but appears to be more limited to histamine, rather than the whole variety of mast cell chemicals, and may have more to do with an inability to breakdown histamine than a condition of mast cell instability. (12)

Symptoms of MCAD

Symptoms of MCAD can be extremely varied and can occur in every system of the body.  Symptoms are often low-grade and chronic and can be episodic with periods of calm and flares. (13)  One of the most important characteristics is that there are multiple symptoms in multiple systems of the body. (13)

Dr. Afrin and colleagues have developed an extensive list of symptoms they have observed with patients and includes the following:

  • Constitutional: fatigue/malaise, weakness, “chronic fatigue syndrome”, subjective and/or objective increased or decreased temperature, “sense of feeling cold much of the time”, sweats (not always nocturnal), flushing, redness or paleness, increased or decreased appetite, early fullness when eating, weight gain or loss, chemical and/or physical environmental sensitivities (often odd)
  • Skin: rashes , freckles, dry skin, warts, skin tags, inflammation of hair follicles, ulcers, eczema, itching, sometimes triggered by exposure to water, stretch marks, streaking on scratching the skin, hair thinning and loss, brittle nails, longitudinal ridges in nails, poor wound healing
  • Lymph: swollen lymph nodes, often changing in size or location, sometimes no symptoms but may be tender, left upper quadrant discomfort in abdomen
  • Lung: nasal inflammation, sinusitis, throat inflammation, bronchitis, lung inflammation or pneumonitis (often confused with infectious pneumonia), cough, difficulty breathing/dyspnea (often low-grade, “I just can’t catch a deep breath”), wheezing, obstructive sleep apnea, pulmonary hypertension
  • Cardiovascular: lightheadedness, weakness, dizziness, vertigo, fainting, postural orthostatic tachycardia syndrome or neurocardiogenic fainting, high and/or low blood pressure, palpitations, abnormal heart rhythms, chest discomfort or pain, atherosclerosis/spasm, heart failure , aneurysms, hemorrhoids, varicose veins, aberrant angiogenesis (cherry angiomas, hemangiomas, arteriovenous malformations, spider veins) , migratory swelling (often non-dependent and with normal cardiac and renal function)
  • Gastrointestinal: swallowing air, swelling (angioedema) in any segment of the GI, difficulty swallowing, bloating/gas, abdominal pain/inflammation (often migratory) , queasiness, nausea, vomiting (sometimes “cyclical”), diarrhea and/or constipation (often alternating), malabsorption (more often selective micronutrient than general protein-calorie malabsorption), abdominal edema/water retention, gastroesophageal reflux disease (often “treatment-refractory”) , inflammatory or irritable bowel syndrome, microscopic colitis
  • Genito-urinary: inflammation of urethra, bladder, or kidney (often migratory), inflammation of vagina or prostate, chronic kidney disease, endometriosis, chronic low back pain or side pain, hydronephrosis , infertility, erectile dysfunction, decreased libido , miscarriages
  • Musculo-skeletal: muscle pain, often diffusely migratory, fibromyalgia , arthritis (typically migratory), joint laxity/hypermobility, diagnosis of Ehlers-Danlos Syndrome Type III, osteoporosis/osteopenia, osteosclerosis, musculoskeletal pain poorly responsive to NSAIDs and narcotics, possible elevated creatine kinase
  • Neurologic: headache (esp. migraine), peripheral sensory and/or motor issues including abnormal sensations, tics, tremors (typically resting) , chronic inflammatory demyelinating polyneuropathy, seizure disorders (can be “treatment-refractory”), pseudoseizures, dysautonomia
  • Endocrine/Metabolic: abnormal electrolytes (including magnesium), abnormal liver function tests, delayed puberty, menstrual cramps, hypothyroidism or hyperthyroidism, abnormal cholesterol/lipids, elevated ferritin, selective vitamin and/or other micronutrient deficiencies
  • Immune: hypersensitivity reactions, autoimmunity, increased susceptibility to infection, elevated or decreased levels of one or more types of immunoglobulin
  • Blood: elevated red blood cell count (polycythemia), anemia (may be macrocytic, normocytic, or microcytic), high or low white blood cell counts, high monocytes, eosinophils or basophils, high or low platelets, clotting disease, easy bruising/bleeding
  • Psychiatric: mood disturbances (g., anger, depression), bipolar affective disorder, attention deficit-hyperactivity disorder, post-traumatic stress disorder, anxiety and panic, psychoses, memory difficulties, word-finding difficulties, other cognitive dysfunction, sleep disruptions (13)

Research is being done into the potential causative role of mast cells in plaque build-up in arteries, because of the pro-inflammatory chemicals (14) as well as in cancer, both from the inflammatory and blood-vessel building effects. (15)  However, the net role of mast cells in cancer development may benefit either the host or the tumor, depending on a variety of factors, including genetics, overall immune health, and the micro-environment of the tumor location. (15)

Because of the effects on the immune system, MCAD may also be associated with an increased risk of autoimmune disease and chronic infection. (11)  There may also be quality of life issues and narcotics risk with chronic pain and malnutrition from intestinal inflammation. (11).

Diagnosis of MCAD

Diagnosis of MCAD is based on symptoms, history, lab testing, response to MCAD-based treatment, and ruling out other possible conditions.  Symptoms and history can be identified by the patient interview and the checklist developed by Dr. Afrin and colleagues. (13) Lab testing can be difficult because of the challenges with many of the lab tests.  First, many of the tests require very specific handling procedures because several of the tests are not heat-stable.  If the samples are not kept chilled for the entire time between collection and analysis, false negative results are highly possible.  Once the sample is provided to the lab, it may be difficult to know if the sample was kept chilled the entire time.

Second, some of the tests need to be run during a flare-up of symptoms which can be difficult for collection; results from samples collected outside a flare-up may show falsely low results. Third, the samples are collected from blood and/or urine, which reflect conditions throughout the body.  A person could still have very significant local mast cell effects while these systemic test results could be negative.  Additionally, many of the local labs I have contacted do not even run some of the tests recommended for MCAD diagnosis.  Given these challenges, I discuss with each patient the advantages and disadvantages of running the different tests that could give us information about MCAD.  Many patients also opt for a trial of MCAD-based therapy to see if symptoms improve.

Treatment of MCAD

MCAD is an extremely complex condition with a myriad of presentations.  As such, I follow the treatment principles outlined by Dr. Afrin:

  • “#1: get patients feeling better, not perfect and not all the time
  • #2: be patient and persistent and use a methodical approach
  • #3: change only one thing at a time
  • #4: start with the cheapest medications and change only as necessary
  • #5: if a patient destabilizes, review what changed over the weeks before to try to identify a cause
  • #6: remember that active and inactive ingredients of medications can cause flare-ups
  • #7: simpler is better
  • #8: if one drug in one class doesn’t work, don’t give up on all the drugs within that class (check inactive ingredients)
  • #9: identify and avoid triggers
  • #10: remember all the other preventative screenings and general health measures” (11)

It is important to keep in mind that “with the exception of classic histamine-related symptoms, at present it is virtually impossible to predict effective therapy for the individual MCAS patient based on the presenting symptoms and findings.” (11)

Identifying and avoiding triggers is crucial to treatment.  Avoiding a flare-up is much easier than trying to calm it once it has started.  However, potential triggers can be extremely varied and the list I’ve compiled from a variety of sources may include:

  • Stress, sympathetic activation, accidents, surgery
  • Sleep deprivation
  • Surgery
  • Sun/heat, temperature changes (especially sudden), pressure/touch
  • “caine” anesthetics, NSAIDs, narcotics, active or inactive ingredients in any medications
  • Aspirin (especially for tryptase-driven issues)
  • Smoking
  • Alcohol, high sugar
  • Oxidative stress
  • Zinc or vitamin C deficiency
  • Excess salt
  • Chronic infection
  • Exposure to allergens
  • Hormone imbalances

Specific treatment for MCAD can include pharmaceuticals, naturopathic treatments, and other supportive therapies.  Pharmaceutical treatments may include:

  • steroids to reduce inflammation;
  • mast cell stabilizers (ketotifen and cromolyn sodium);
  • histamine blockers for histamine-related symptoms;
  • leukotriene blockers; and
  • medications to manage symptoms, such as pain or anxiety. (11)

There are some medications that have some anecdotal use, and some that theoretically could be helpful but there is no MCAD-specific data on their efficacy.  (11) There are also some medications that are still in clinical trials and could become options in the future.

Naturopathic treatments include:

  • evaluation of diet, especially for high histamine, high histidine, and high salicylate foods;
  • evaluation of intestinal bacterial balance because certain types of bacteria produce histamine while others break it down (16);
  • herbal and nutritional mast cell stabilizers;
  • anti-inflammatory herbs and nutrients;
  • treatment to support histamine breakdown, especially via methylation; and
  • lactoferrin especially for tryptase and heparin.

Other therapies may be non-medication ideas for symptom support and/or stabilization.  For example, for a patient with low blood pressure, maintaining consistently adequate water intake and electrolytes along with wearing compression garments might be helpful.

I also feel that part of naturopathic treatment is patient advocacy.  The understanding of MCAD in the medical field is still emerging and many practitioners are not aware of the condition or diagnosis.  Many patients are told their symptoms are “all in their heads”; while MCAD can cause many neurologic and psychiatric symptoms, there is a true physiological basis for what MCAD patients are experiencing.

Understanding and treating MCAD takes patience and perseverance, and with both, significant improvements can be made for people who never had answers before.












(11) Afrin, L. Never Bet Against Occam: Mast Cell Activation Disease and the Modern Epidemics of Chronic Illness and Medical Complexity. 2016


(13) Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol2014; 3(1): 1-17





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