Mast Cell Activation Syndrome

 

The mast cell is a potent immune cell known for its functions in host defence responses and diseases, such as asthma and allergies.  They are immune cells of the myeloid lineage and are present in connective tissues throughout the body.   The activation and degranulation of mast cells significantly modulates many aspects of physiological and pathological conditions in various settings.   With respect to normal physiological functions, mast cells are known to regulate vasodilation, vascular homeostasis, innate and adaptive immune responses, angiogenesis, and venom detoxification.  On the other hand, mast cells have also been implicated in the pathophysiology of many diseases, including allergy, asthma, anaphylaxis, gastrointestinal disorders, many types of malignancies, and cardiovascular diseases. (1)

 

This review discussion is simply to point out current knowledge of the diversity of problems associated with mast cell activation, and an analysis of current and evolving management.  The implications to specific problems, especially fibromyalgia, POTS and dysautonomia are discussed in the separate article on Mast cell Activation Management.  In respect to the work by Lawrence Afrin, and the reproduction of his findings, this article follows closely the layout in his article: Presentation, Diagnosis and Management of Mast Cell Activation Syndrome. (5)

 

Managing POTS using a detailed timeline and working out activators and drivers to the syndrome does provide a way of tackling MCAS by reducing the impact of the drivers themselves rather than depending on medication.    By looking at diet, mechanical, environmental factors such as trauma, emotional stress, vascular compression, posture, and spine drivers with activation of pain pathways, symptoms can be dramatically improved.    The impact of high- level acupuncture must not be forgotten, as this does appear to turn down the inflammatory responses, while the mechanical and other causes are worked through.

 

“Mast cells play a key role in homeostatic mechanisms and surveillance, recognizing and responding to different pathogens, and tissue injury.   An abundance of mast cells reside in connective tissue that borders with the external world (the skin as well as gastrointestinal, respiratory, and urogenital tracts.)   Situated near nerve fibres, lymphatics, and blood vessels, as well as coupled with their ability to secrete potent mediators, mast cells can modulate the function of local and distant structures (eg other immune cell populations, fibroblasts, angiogenesis), and mast cell dysregulation has been implicated in immediate and delayed hypersensitivity syndromes, neuropathies, and connective tissue disorders.” (2)

 

Mast cells are involved in many immune reactions and diseases through:

  1. The expressions of several receptors,
  2. Production of various mediators such as histamine, cytokines, and chemokines,
  3. Direct interactions with immune cells.

 

Besides allergic diseases, mast cells have been also assumed to be involved in autoimmune diseases such as bullous pemphigoid, rheumatoid arthritis, and multiple sclerosis. Moreover, several studies reported the involvement of mast cells in collagen disease.   Mikita et al in 2017 reviewed recent findings about the role of mast cells especially in systemic lupus erythematosus and systemic sclerosis and found that in these diseases, mast cells seem to be involved in local inflammation and tissue damage partially in the targeted organ rather than the development of autoimmunity including production of autoantibodies. (3)

 

In the past years, accumulating evidence established the contribution of the mast cell to cardiovascular diseases as well, in particular, by its effects on atherosclerotic plaque progression and destabilization. Through its release not only of mediators, such as the mast cell–specific proteases chymase and tryptase, but also of growth factors, histamine, and chemokines, activated mast cells can have detrimental effects on its immediate surroundings in the vessel wall. This results in matrix degradation, apoptosis, and enhanced recruitment of inflammatory cells, thereby actively contributing to cardiovascular diseases.  (4)

 

First recognized in 1991 and finally labeled in 2007, Mast Cell Activation Syndrome (MCAS) is a large collection of diseases resulting from inappropriately activated mast cells.   If differs from the rare and very dangerous “mastocytosis” as it is not proliferating, but due to the marked diversity of biological effects caused by the inflammatory mediators released by the mast cells, MCAS typically presents as chronic, persistent or recurrent, or slowly progressive multisystem inflammatory problem.    It is usually acquired early in life by the interaction of environmental with inherited risk factors.   Virtually all of the syndrome’s manifestations are non-specific, leading to decades of mysterious illnesses and often incorrect diagnoses.  “A large menagerie of mutations in mast cell regulatory elements has been found in MCAS patients, with no clear patterns, or genotype-phenotype correlations apparent,” driving the heterogenicity of the clinical presentations.   All of the body’s systems can be affected, and there is often great difficulty in detecting definite measureable evidence to confirm this.  (5)

 

Systemic mastocytosis usually drives significantly elevated levels of Tryptase, while MCAS usually has normal tryptase, although other indicators eg histamine, specific prostaglandins and other markers may be altered.  Therapies against MCAS generally aim to control symptoms by inhibiting abnormal mediator production and release, and managing the consequences of these.   Unlike systemic mastocytosis, lifespan on people with MCAS is usually normal, although quality of life can be severely affected.   But systemic mastocytosis, which is a rare, is the tip of the iceberg of mast cell diseases.

 

Although symptoms can appear at any age, most commonly as a child or adolescent, sometimes in a neonate or infant, the diagnosis is unsuspected due to the non-specific nature of the symptoms. (5)   Most patients live their lives without the underlying diagnosis being made.  There are usually seen as chronically multi-systemically ill, perhaps being recognized as having an inflammatory disease, but with typical testing unable to localize the actual cause.   History will usually provide a “trigger point” but in depth history will usually show earlier unrecognized symptoms.   These can be as varied as gastrointestinal dysfunction, presenting with diarrhoea, or constipation, or disorders of erythropoiesis.   Successful management of these requires a detailed timeline of disorders that track back to infancy.

 

Fatigue and malaise are the most common complaints in MCAS. (5)  Most patients remain functional, but some are severely impaired.   Low-grade temperature dysregulation is not uncommon, as are lymph node swelling, weight loss, unexplained weight gain, loss of appetite, fluctuating oedema, but it is the gain in adipose tissue that accounts for weight increase in most MCAS.(5)   Again, there is often an identifiable acute stressor in the months prior to the weight gain.    These patients may have bariatric surgery sometimes with complications of poor wound healing, and while there is initial weight loss, the other symptoms usually remain, and the weight gain slowly starts to return. (5)    Mast cells are programmed to site themselves at environmental interfaces- lungs, gut, skin, bladder, nose and sinuses etc, so there can be a wide range of pathology in aberrant mast cell activation.

 

Dermatological Manifestations

 

Pruritis is a common complaint, which can be episodic or constant, often unpredictably migratory, and sometimes controlled with simple anti-histamines, but it too can be disabling.   It can be generalized, eg aquagenic pruritis,or localized, or migratory. (5)    Drug reactions can be from dyes and fillers in medications rather than the medication itself, and in these times of generic substitution, this can create difficulties localizing driving forces.    Symptoms can vary with environmental changes, with reactions as complex as close exposure to venetian blinds, or UV light.   This can be complicated by things such as reactions to pollens and similar environmental triggers.

 

Skin changes such as xerosis, fragility and telangiectasia, unpredictable migratory patchy rashes are common, as are warts and spontaneous folliculitis.    Unexplained painful sensitive skin is not uncommon, nor is dermatographism.   Wound healing is often impaired, with unexpected scarring.   Striae may occur, especially in younger patients, often seen about the trunk, abdomen, axillae and sometimes costo-vertebral angles. (5)

 

Opthalmological Manifestations

 

Most commonly symptoms reflect generally non-infectious inflammation, the most common dry, itchy eyes.   Chronic or episodic excessive lacrimation, scleritis, blepharitis, conjunctivitis also occur, as can lid tremors and tics.   Not infrequently patients complain of acute episodes of inability to focus, lasting minutes to hours, often with flares of other symptoms especially fatigue. (5)

 

Otological, Oral and Sinonasal Manifestations

 

Otological symptoms are usually also of non-infectious inflammation, with otitis media especially in children, painful and/or itchy canals is not uncommon.  Patients can experience hearing aberration, tinnitus, hyperacuris with often little to explain symptoms. (5)

 

Some of the highest concentrations of mast cells are in the sinonasal passages.  A chronic sense of congestion is often reported.   There may be intermittent ulcerations, sores, olfactory intolerances, and unprovoked, often severe epistaxes are not uncommon.(5)

 

Intermittent oral or labial discomfort to pain is not uncommon, focal sometimes migratory, or diffuse, abnormal taste, ulcerations, or a diffuse burning discomfort can be found with negative biopsies for Sjogren’s Syndrome, the latter usually in response to a stressor, and leading many patients to be mistakenly diagnosed as having psychiatric illness.

 

Chronic or intermittent angioedema of the oral tissues are sometimes seen.     Dental decay in spite of good dental hygiene is not uncommon, but the connection between stressor and dental problem is usually not seen due to the slower pace of development of the dental problems.

 

Pulmonary Findings

 

One of the major inflammatory mediators produced by mast cells is prostaglandin D2 (PGD2), a strong bronchoconstrictor, 10- times more potent than histamine, so the most common complaint is irregularly episodic dyspnoea, sometimes accompanied by wheezing, but where chest imaging and pulmonary function testing is usually unrevealing.  They may be diagnosed as “reactive airways disease.”   Mast cell activation may be part of the progression of emphysema and chronic obstructive pulmonary disease, as well as pulmonary hypertension. (5)

 

Cardiovascular Findings

 

Current evidence points towards a key role for mast cells as effector cells in atherosclerosis and acute cardiovascular syndromes.   The many mechanisms involved include secretion of the proteases chymase and tryptase, histamine, growth factors and cyto- and chemokines eg TNF-a, interferon-g, interleukin-6 and interleukin-8 by activated mast cells.   Mast cell activation leads to increased plaque progression and destabilization. (4)

 

Cardiac, vasomotor, and vasculospastic issues occupy the entire spectrum of possible abnormalities.  Palpitations are very frequent, resting tachycardia quite common, sometimes bradycardia.  There can be unpredictable episodes of both hypotension and hypertension, unlike phaeochromocytoma with its tachycardia and hypertension.    Noradrenalin is a known potent vasoconstrictor, and the mast cell provides one of the cellular sources of this.   PGD2, whose dominant source is the mast cell, is more potent a vasoconstrictor than noradrenalin in certain vascular beds, but can act as a vasodilator in others. (5)

 

Presyncope is common, but frank syncope fairly uncommon.   Episodes are described as sudden-onset “lightheadedness, weakness, dizziness and occasionally vertigo.”    Tilt table testing may suggest postural orthostatic tachycardia syndrome (POTS). (5)

 

Chest pain is sometimes described.   Two uncommon chest pain syndromes are thought to be associated with mast cell activation- Kounis Syndrome (allergic angina or allergic myocardial infarction) in the absence of obstructive coronary lesions is thought to be from mast cell activation, and requires identification of the allergic insult.    Takotsubo syndrome (acute stress-induced cardiomyopathy with a hyperkinetic cardiac base, hypokinetic mid-ventricle and apex, and left ventricular apical ballooning) is seen in 2% of suspected acute coronary syndromes.   75% of Takotsubo cases have elevated plasma catecholamines. (5)

 

Mast cell activation syndrome-driven coronary and peripheral arteriosclerosis producing true vaso-occlusive pain can be aggressive even at a young age.  (5)

 

Oedema is commonly found, often with normal cardiac function, and this can be episodic in nature, and move from one limb to the other, or elsewhere in the body eg periorbital. (5)

 

Gastrointestinal Findings

 

Oesophagitis is common, often refractory to acid reduction therapy.  Gastritis and small and large bowel enteritis are common, manifest as migratory abdominal pain, diarrhoea, constipation, often alternating.  Chronic or intermittent nausea and vomiting is common.   These are usually diagnosed as Irritable Bowel Syndrome.   Selective micronutrient malabsorption, especially iron, but including copper and B vitamins is common.   Lawrence Adfrin (5) advocates H1/H2 histamine receptor blockade. (5)

 

Inflammation and/or fibrosis in pancreatic exocrine glands and/ or pancreatic ducts is thought to be part of the MCAS-driven inflammatory disease, where 40% of causes of chronic pancreatitis are “idiopathic” and increasingly thought to be auto-immune. (5)

 

Around 50% of MCAS patients have evidence of hepatic damage, with fibrosis the most common pathological finding.  Cholestasis and portal hypertension are uncommon, but when the latter is present, is reflected in gastroesophageal varices and splenomegaly. (5)

 

Elevated levels of mast cell inhibitors are commonly not detectable unless the patient is markedly symptomatic.   Occasionally mast cells are seen in biopsies from the GI tract and labelled “mastocytic enterocolitis.”   40% of patients with “gastroesophageal reflux disease” are refractory to maximal dose PPI, remaining symptomatic despite no significant acid production, therefore it is not acid production causing their symptoms.   Biopsies are usually normal, or mild to moderate chronic inflammation, raising the possibility that these are a manifestation of mast cell disease. (5)

 

Genitourinary Findings

 

Interstitial cystitis and chronic recurrent prostatitis are common presentations, with sterile mast cell –driven dysuria.   Vaginitis may also be present, as can renal inflammation and/or fibrosis.  Acute and chronic renal failure can occur from obstructive uropathies, and if these are intermittent with no identifiable stones, obstructive ureteral angioedema may be occurring. (5)

 

Inflammatory mediators can cause aching and pain, often vague in location, and often causing chronic low back pain. (5)

 

Aberrant mast cell activation has been recognized to be a primary issue in endometriosis, affecting 15 to 20% of women in reproductive years. (5)   Miscarriages in MCAS, especially if associated with an abnormal prothrombin time or partial thromboplastic time should be checked for MCAS-driven antiphospholipid antibody syndrome. (5)

 

Musculoskeletal and Joint Findings

 

Premature osteopenia/osteoporosis is frequently found, and occasionally osteosclerosis.   This is thought to be from excessive RANKL-stimulated osteoclast activity with increased bone resorption. (5)

 

Diffuse, diffusely migratory aching and arthralgia is common, which may attract duagnoses or osteoarthritis, seronegative rheumatoid arthritis, fibromyalgia and polymyalgia rheumatica.   It can be centered in bones or soft tissue with no radiological abnormality.      There has been some evidence that mast cell dysfunction is associated with complex regional pain syndrome. (5)

 

Excessive joint laxity /hypermobility is sometimes seen suggesting Ehlers-Danlos Syndrome, but with negative testing for known mutations.   This group also is subject to POTS. (5)

 

MCAS-driven pain often responds poorly to traditional analgesics, both non-steroidal or narcotics, and both of these can trigger flares of symptoms, and some respond to MC-directed treatment eg anti-histamines, cromolyn and bisphosphonates. (5)

 

Neuropsychiatric Findings

 

Mast cells are situated in proximity to nerves as well as environmental interfaces, and it is becoming apparent that inflammation is a significant factor in the development of neurologic and psychiatric disorders. (5)

 

Headaches are common, often disabling, including migraine where mast cell degranulation has been implicated.   Vasomotor instability can be the principle symptom, leading to diagnoses of dysautonomia and POTS.   Not uncommonly there are increased sensory and/or motor nerve activity reflected in paraesthesiaes and tics.   Sometimes essential resting tremors are present, and acute presyncope can occur.    While EMGs and nerve conduction tests are usually normal, occasionally testing suggests “chronic demyelinating polyneuropathy (CIDP), sometimes accompanied by a modest monoclonal gammopathy of undetermined significance, which is felt by Lawrence Afrin to be MCAS-driven. (5)

 

Afrin also believes that mast cells are involved in the development of multiple sclerosis and amyotrophic lateral sclerosis, with PGD2 inducing motor neurone loss through demyelination and enhanced astrogliosis.   He describes symptom improvement with PGD2 receptor blockade.   He also describes evidence of mast cell involvement in Alzheimers disease. (5)

 

Obstructive sleep apnoea is common in MCAS, as is sleep abnormality. (5)

 

Afrin describes episodic cognitive dysfunction (brain fog) as the most common psychiatric issue in MCAS, particularly affecting short-term memory and word-finding.   Some patients find their overwhelming fatigue is the issue.   Mood disorders, irritability, anger, depression, bipolar affective disease, attention deficit disorder, anxiety and panic attacks are not uncommon. (5)

 

Stressful events often trigger acute and chronic flares of MCAS, and makes a diagnosis of PTSD common. (5)

 

Mast cell activation appears to play a role in the etiology of autism spectrum disorders (ASD), with most ASD patients having food intolerance and other allergic symptoms. (5)

 

Endocrine / Metabolic Findings

 

TSH elevation is common, and hyperthyroidism less commonly.  Elevated anti-thyroid antibodies are often detectable, sometimes high levels of titre are detected with no apparent thyroid disease.(5)

 

Elevated ferritin is known to be released by hepatocytes and macrophages, but elevated ferritin can also be released from mast cells, often misinterpreted as haemochromatosis. (5)

 

Obesity and diabetes mellitus are both clearly associated with mast cell disease, with both recognized as being inflammatory.   Metabolites of PGD2 figure in at least one key adipose management pathway, so lipid abnormalities are common in MCAS.   Statin-resistant lipid elevation can sometimes be corrected by MCAS-targetted therapy. (5)

 

Haematological Findings

 

MCAS is classified as a haematological disease presents with few to no significant haematological abnormalities in most cases.    Part of the answer is that mast cells spend little of their lifespan in the marrow, leaving the marrow early, circulating briefly then residing for the remainder of their relatively long lifespan of several months to years, in peripheral tissues.    The clinical presentation of MCAS is entirely dependent on which mediators are being aberrantly released. (5)

 

Serum tryptase levels are more reflective of the total body load of mast cells and their activation state.   But as MCAS id a relatively non-proliferative disease, most patients have normal tryptase levels.   Afrin believes that levels 20% above baseline as highly suggestive of MCAS. (5)

 

The most common abnormality in peripheral blood is monocytosis, usually relative rather than absolute elevation, and often considered diagnostically insignificant.   Persistent eosinophilia or “reactive lymphocytes” may also be seen.  Thrombocytosis or thrombocytopaenia  may also be present.    The heterogenicity of these abnormalities across the MCAS population is thought by Lawrence Afrin to be likely due to the mutational heterogenicity of the disease.   In thrombocytosis JAK2 analysis associated with the classic BCR/ABL-1 negative chronic myeloproliferative neoplasms may be positive or negative.   There is a propensity for MCAS patients to develop haematological malignancies of any kind, he feels it possible for a JAK-2 positive MPN to have developed secondary to mast cell disease.    (5)

 

MCAS patients may have increased or decreased red cells.  Erythrocytosis is usually modest but can be misdiagnosed as polycythaemia vera, but have little response to phlebotomy.   As hydroxyurea helps control some aberrant mast cells this may provide better responses.    The erythrocytosis of MCAS is typically macrocytic, but the mechanism unclear.    Anaemia is the most common erythrocytic abnormality seen, and can be macrocytic, microcytic, or normocytic.   In the more severe macrocytosis, B12 deficiency is the most common cause, and ideally patients should be assessed for anti-intrinsic factor Ab and anti-parietal cell Ab.  A deteriorating microcytic anaemia in a MCAS patient is most commonly iron but copper deficiency is possible as well.   In iron-deficiency, once chronic bleeding has been excluded is often corrected by H1/H2 histamine receptor blockade.   PPIs are commonly used to treat the reflux symptoms from the MCAS disease and can inhibit acid production sufficiently to affect iron absorption. (5)

 

Copper deficiency is usually the result of selective copper malabsorption, but possible zinc toxicity  (which causes copper toxicity) should be checked. (5)

 

The bone marrow is usually normal in MCAS patients, but can show a non-specific, mild myeloproliferative/myelodysplastic appearance. (5)

 

Coagulopathic Findings

 

The bleeding most commonly seen by Lawrence Afrin in MCAS patients is “easy bruising” and intermittent unprovoked epistaxes.    Surprisingly, menses may be normal.   Some only have abnormal bleeding in surgical and non-surgical trauma, where bleeding is confined to the traumatized site.   Thromboembolism is not rare, often without any coagulation system abnormality. (5)

 

Immunologic Findings

 

Both cellular and humoral immune abnormalities are common in MCAS, leading to impairments in any or all of the primary functions of the immune system. Leading to increased susceptibility to infection, increased development of auto-immune disease, impaired healing and increased risk of malignancies of all types.   Acute, subacute and delayed hypersensitivity reactions can be seen. (5)

 

Investigations

 

  • FBC, differential
  • E’s &LFTs
  • Se magnesium
  • Immunoglobulins (if problems with infections
  • PTT, PT (if bleeding, bruising, thromboembolic events
  • Se Tryptase (highly specific mast cell mediator)
  • Se Chromogranin A (mast cell product- but also altered by heart failure, renal insufficiency, PPI usage, neuroendocrine malignancy)
  • Plasma histamine (less specific than tryptase as also released by basophils)
  • Chilled plasma PGD2

 

 

Management of Mast Cell Activation Syndrome

 

Avoidance of triggers, desensitization when specific unavoidable environmental abnormalities are present, and prophylactic therapies (eg bisphosphonate therapy for osteoporosis) can limit morbidity.   Because of potential circulation of released mediators, and potential interaction of released mediators with elements of the nervous and hormonal/endocrine systems, the dysfunctional mast cells releasing the mediators causing symptoms may or may not be located proximately to the affected site.   This therapies aim to:

  1. Reduce mast cell production and release of mediators
  2. Interfere with released mediators
  3. Counter the effects of the released mediators.

 

The extreme underlying mutational heterogenicity of the disease almost certainly leads to extreme heterogenicity in patterns of mediator production and release, in turn leading to extreme heterogenicity of clinical presentation and responsiveness to therapeutic agents.In view of the disease complexity and the inherent propensity to react adversely to potentially any new exposure, it is important to make only change in therapy at a time.

 

Virtually all commercial products have various fillers and dyes which may be inert in normal people but can affect MCAS patients.   In patients who react to wide ranges of fillers and dyes, products can usually be compounded. (5)

 

Medications:

 

  1. Inhibition of mediator production
    1. Corticosteroids may be helpful but limited by toxicities
    2. NSAIDs and aspirin. NSAIDs can be helpful, but these can also trigger flares of activation.

 

  1. Inhibition of mediator release (mast cell stabilization)
    1. Benzodiazepines to address end organ receptors as well as mast cells, added to potential improvement from reduced anxiety in some inflammatory bowel disease. Also may be helpful in the emergency management of the disease, especially the shorter half-life products eg loraxepam, clonazepam or alprazolam.
    2. Tricyclics eg doxepin have H1 receptor blocking effects that can be added to traditional antihistamines.
    3. SSRIs may benefit the associated depression but also can affect mast cells via surface serotonin reuptake transporters. However adding antihistamines to SSRIs brings the risk of serotonin syndrome.
    4. Zolpidem also targets the benzodiazepine receptor, independent of whether other benzodiazepines are in use. Helpful in the associated insomnias, but not in other MCAS symptoms.   No role in emergency management.
    5. Cromolyn (Intal) can stabilize mucosal mast cells- for dosage regime see page 199 of “Presentation,Diagnosis and Management of Mast Cell Activation Syndrome.”
    6. Oral Ketotifen-originally marketed as an inhibitor of anaphylaxis, it inhibits release and/or activity of mast cell and basophil mediators including histamine, neutrophil and eosinophil chemotactic factors, arachidonic acid metabolites, prostaglandins and leukotrienes. (6) It is available in Australia as Zaditen eye drops, and would have to be compounded to be taken orally with a dose of 1 mg twice daily increasing weekly as tolerated.
    7. Quercetin is a flavonoid that is poorly absorbed but is thought to inhibit lipooxygenase and cyclooxygenase reducing production of inflammatory mediators eg leukotrienes and histamine. It seems to have general anti-inflammatory effects and impedes PGD2-driven flushing.   General dosing is 500 to 1000 mg twice daily.
    8. Allergen-driven cross-linking of multiple IgE molecules bound to mast cell-surface IgE receptors is a major route of mast cell activation. Omalizumab (Xolair) is a humanized monoclonal antibody which reversibly binds the Fc portion of IgE hindering IgE binding with its mast cell-surface receptor.
    9. Rarely hydroxyurea and immunosuppressants

 

  1. Blockade of released mediators
    1. Histamine H1 and H2 blockade to address end organ receptors as well as mast cells
    2. Leukotrienes are synthesized and released by mast cells –Selective leukotriene receptor antagonists eg Singulair 10 mg 1-2times daily may help- limited in hepatic involvement.
    3. Bisphosphonates are helpful in excessive bone resorption. Prolia has demonstrated efficacy in osteopenic/osteoporotic situations, and should be effective in the MCAS-associated osteoporosis.
    4. Tumour necrosis factor (TNF) alpha is a well-established mast cell mediator product, and TNF-alpha antagonists eg etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicabe) are approved for use in a variety of systemic inflammatory diseases increasingly suspected to be of aberrant mast cell orogin (eg rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease). There have been no trials in any other mast cell diseases.

 

  1. Other:
    1. Pancreatic enzyme supplements may be helpful in chronic pancreatitis where there is chronic diarrhoea, weight loss, and micronutrient malabsorption. (5)

 

Conclusion

 

The diversity of problems associated with mast cell activation has significant implications many complex medical problems such fibromyalgia, POTS, dysautonomia and auto-immune disease, and may be important in real cause of diseases such as diabetes, hypertension, cardiomyopathy, COPD, vascular disease and auto-immune disease just to name a few.

 

These are all inflammatory processes with multiple causes, most importantly genetic, and it is injury, lifestyle and similar factors which steers you into whatever disease you may develop, dependent on your individual DNA.   Medicine is a constantly evolving science, and I have no doubt further research will unlock even more causes, or at least provide better explanations for the disease processes.

 

 

References:

  1. Krystel-Whittemore, M., Dileepan, K., Wood, J.G.. Mast Cell: A Multi-Functional Master Cell, 2016. https://www.frontiersin.org/articles/10.3389/fimmu.2015.00620/full
  1. Seneviratne,S.L., Maitland, A., Afrin A.: Mast Cell Disorders in Ehlers-Danlos Syndrome. 2017, American Journal of Medical Genetics Part C, 175C: 226- 236
  1. Mikita, n., Inaba, Y.,Yoshimasu, T., Kanazawa, N., Furukawa, F.: Mast Cells in Collagen Diseases. 2017. https://www.researchgate.net/publication/319359864_Mast_cells_in_collagen_diseases
  1. Bot, I., Shi, G., Kovanen, P.,Mast Cells as Effectors in Atherosclerosis. 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304944/
  1. Afrin, L. Presentation,Diagnosis and Management of Mast Cell Activation Syndrome. 2013. Nova Science Publishers,Inc.
  1. Sokol,K.,Amar, N., Starkey, J., and Grant, A.: Ketotifen in the management of chronic urticaria: resurrection of an old drug. 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309375/

 

Mast Cell Activation and Inflammation in Disease

 

There is an increasing knowledge that mast cells play a vital role in normal physiology of our body and our ability to deal with body threats, but when there is aberrant mast cell activation, it can result in a wide spectrum of problems, especially documented in POTS (Postural Orthostatic Tachycardia Syndrome) and, I believe in dysautonomia and fibromyalgia.   Symptoms produced by mast cell activation (Syndrome, or MCAS, as opposed to the very dangerous Mast Cell Disease), is determined largely by a person’s DNA, so when dealing with mast cell associated problems, there simply is no one size fits all, or one medication to control symptoms.

 

Dealing with POTS is complex and difficult, and while MCAS is present, I have no doubt we will find other as yet unknown drivers.   Knowledge of this does give us a direction that helps most, and from this, how to deal with other complex medical problems.   It also makes one challenge many of the current medical beliefs in hypertension for example.

 

The mast cell is a potent immune cell known for its functions in host defence responses and diseases, such as asthma and allergies.  They are immune cells of the myeloid lineage and are present in connective tissues throughout the body.   The activation and degranulation of mast cells significantly modulates many aspects of physiological and pathological conditions.  (1)

 

Degranulation is a cellular process that releases antimicrobial cytotoxic or other molecules from secretory vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including granulocytes(neutrophilsbasophils, and eosinophils) and mast cells. It is also used by certain lymphocytes such as natural killer (NK) cells and cytotoxic T cells, whose main purpose is to destroy invading microorganisms. (6)

 

Antigens interact with IgE molecules already bound to high affinity Fc receptors on the surface of mast cells to induce degranulation, via the activation of tyrosine kinases within the cell. The mast cell releases a mixture of compounds, including histamineproteoglycans, serotonin, and serine proteases from its cytoplasmic granules.   (6)

 

In immunology, an antigen is a molecule capable of inducing an immune response (to produce an antibody) in the host organism.   Sometimes antigens are part of the host itself in an autoimmune disease.   Antigens are “targeted” by antibodies. Each antibody (immune response) is specifically produced by the immune system to match an antigen after cells in the immune system come into contact with it; this allows a precise identification or matching of the antigen and the initiation of a tailored response. The antibody is said to “match” the antigen in the sense that it can bind to it due to an adaptation performed to a region of the antibody; because of this, many different antibodies are produced, each with specificity to bind a different antigen while sharing the same basic structure. In most cases, an adapted antibody can only react to and bind one specific antigen; in some instances, however, antibodies may cross-react to and bind more than one antigen. (6)

 

With respect to normal physiological functions, mast cells are known to regulate vasodilation, vascular homeostasis, innate and adaptive immune responses, angiogenesis, and venom detoxification.  On the other hand, mast cells have also been implicated in the pathophysiology of many diseases, including allergy, asthma, anaphylaxis, gastrointestinal disorders, many types of malignancies, and cardiovascular diseases. (1)

 

“Mast cells play a key role in homeostatic mechanisms and surveillance, recognizing and responding to different pathogens, and tissue injury.   An abundance of mast cells reside in connective tissue that borders with the external world (the skin as well as gastrointestinal, respiratory, and urogenital tracts.)   Situated near nerve fibres, lymphatics, and blood vessels, as well as coupled with their ability to secrete potent mediators, mast cells can modulate the function of local and distant structures (eg other immune cell populations, fibroblasts, angiogenesis), and mast cell dysregulation has been implicated in immediate and delayed hypersensitivity syndromes, neuropathies, and connective tissue disorders.” (2)

 

Mast cells are involved in many immune reactions and diseases through:

  1. The expressions of several receptors,
  2. Production of various mediators such as histamine, cytokines, and chemokines,
  3. Direct interactions with immune cells.

 

Besides allergic diseases, mast cells have been also assumed to be involved in autoimmune diseases such as bullous pemphigoid, rheumatoid arthritis, and multiple sclerosis. Moreover, several studies reported the involvement of mast cells in collagen disease.   Mikita et al in 2017 reviewed recent findings about the role of mast cells especially in systemic lupus erythematosus and systemic sclerosis and found that in these diseases, mast cells seem to be involved in local inflammation and tissue damage partially in the targeted organ rather than the development of autoimmunity including production of autoantibodies. (3)

 

In the past years, accumulating evidence established the contribution of the mast cell to cardiovascular diseases as well, in particular, by its effects on atherosclerotic plaque progression and destabilization. Through its release not only of mediators, such as the mast cell–specific proteases chymase and tryptase, but also of growth factors, histamine, and chemokines, activated mast cells can have detrimental effects on its immediate surroundings in the vessel wall. This results in matrix degradation, apoptosis, and enhanced recruitment of inflammatory cells, thereby actively contributing to cardiovascular diseases.  (4)

 

First recognized in 1991 and finally labeled in 2007, Mast Cell Activation Syndrome (MCAS) is a large collection of diseases resulting from inappropriately activated mast cells.   If differs from the rare and very dangerous “mastocytosis” as it is not proliferating, but due to the marked diversity of biological effects caused by the inflammatory mediators released by the mast cells, MCAS typically presents as chronic, persistent or recurrent, or slowly progressive multisystem inflammatory problem.    It is usually acquired early in life by the interaction of environmental with inherited risk factors.   Virtually all of the syndrome’s manifestations are non-specific, leading to decades of mysterious illnesses and often incorrect diagnoses.  “A large menagerie of mutations in mast cell regulatory elements has been found in MCAS patients, with no clear patterns, or genotype-phenotype correlations apparent,” driving the heterogenicity of the clinical presentations.   All of the body’s systems can be affected, and there is often great difficulty in detecting definite measureable evidence to confirm this.  (5)

 

Systemic mastocytosis usually drives significantly elevated levels of Tryptase, while MCAS usually has normal tryptase, although other indicators eg histamine, specific prostaglandins and other markers may be altered.  Therapies against MCAS generally aim to control symptoms by inhibiting abnormal mediator production and release, and managing the consequences of these.   Unlike systemic mastocytosis, lifespan on people with MCAS is usually normal, although quality of life can be severely affected.   But systemic mastocytosis, which is a rare, is the tip of the iceberg of mast cell diseases.

 

Although symptoms can appear at any age, most commonly as a child or adolescent, sometimes in a neonate or infant, the diagnosis is unsuspected due to the non-specific nature of the symptoms. (5)   Most patients live their lives without the underlying diagnosis being made.  There are usually seen as chronically multi-systemically ill, perhaps being recognized as having an inflammatory disease, but with typical testing unable to localize the actual cause.   History will usually provide a “trigger point” but in depth history will usually show earlier unrecognized symptoms.   These can be as varied as gastrointestinal dysfunction, presenting with diarrhoea, or constipation, or disorders of erythropoiesis (the process of producing red blood cells).   Successful management of these requires a detailed timeline of disorders that track back to infancy.

 

Fatigue and malaise are the most common complaints in MCAS. (5)   Most patients remain functional, but some are severely impaired.   Low-grade temperature dysregulation is not uncommon, as are lymph node swelling, weight loss, unexplained weight gain, loss of appetite, fluctuating oedema, but it is the gain in adipose tissue that accounts for weight increase in most MCAS. (5)   Again, there is often an identifiable acute stressor in the months prior to the weight gain.    These patients may have bariatric surgery sometimes with complications of poor wound healing, and while there is initial weight loss, the other symptoms usually remain, and the weight gain slowly starts to return. (5)    Mast cells are programmed to site themselves at environmental interfaces- lungs, gut, skin, bladder, nose and sinuses etc, so there can be a wide range of pathology in aberrant mast cell activation.

 

Inflammation

 

Inflammation, to me, is at the basis of most disease.  Inflammation, the immune response of body tissues to injury or infection, has been an important part of our innate immunity since we were cavemen.     Acute inflammation is a normal process that protects and heals the body following physical injury or infection. However, if the agent causing the inflammation persists for a prolonged period of time, the inflammation becomes chronic, which can cause a wide range of problems.

 

Current disease research revolves around the TLR Receptors (Toll-like receptors) as being threat response receptors activated by threats to the body, whether this be trauma, food (or alteration in our food such as GM and preservatives) we are intolerant of, even stress etc- which provokes an immune response, causing the typical symptoms of IBS, chronic fatigue, migraine, dysautonomia, fibromyalgia, reflux oesophagitis to name but a few.     Working out the things that are triggering the TLRs, and activating the mast cells in an aberrant manner, is critical to dealing with these problems.

 

The spine is a major factor in triggering TLRs, especially in migraine and fibromyalgia.    This is obvious in people following whiplash and other spinal injury, but it also can be occupational, for example in hairdresser, dentists, nurses, who work with a rotated spine.   There is likely to be an increase over future years as people become more dependant on their computers and tablets, while their posture is not attended to.

 

When stress is less (with consequent reduction in activation of TLR’s,) we can often eat the trigger foods, or small quantities, so sometimes it is hard to work out the culprits.   Symptoms often disappear when stress is not present, so many people are considered to have only psychological problems, which is often far from reality.

 

The vascular compression syndromes, most prominently the popliteal and thoracic outlet syndromes are co-factors of uncertain significance in the symptomatology in POTS  (Postural Orthostatic Tachycardia Syndrome), but it cannot yet be proven that they are the underlying cause.     It is thought that special receptors called baroreceptors that line the adventitia of vessels react to stretching or compression, releasing inflammatory chemicals.

 

Exactly what is released is the subject of current research on the Gold Coast.   Clues can be found by inducing compression while measuring heart rate variability, and early studies here are revealing different patterns of catecholamine release.   Catecholamine, any of various naturally occurring amines (members of a family of nitrogen-containing organic compounds derived from ammonia ) including dopamine, epinephrine (adrenaline), and norepinephrine (nor-adrenaline); and a local chemical mediator, histamine.

 

In a similar vein, increasingly diseases such as endometriosis are becoming recognized as “auto-immune” diseases, and there is an evolving interest in Pelvic Congestion Syndrome, where veins in the pelvis are dilated, so the mechanisms of inflammation from these would appear to be mechanical, thus offering clinicians yet another direction to management of disease such as Fibromyalgia, POTS, Migraine and Hashimotos Disease, where vascular compression syndromes are being found in the majority of patients, again suggesting disease activation by production of  catecholamines when the vessels are stretched or compressed.

 

Potentially more serious, microemboli and/or inflammatory cascades may be released as the venous blood which has been stagnant when the vein has been compressed for a period of time, is released back into the circulation.   D-Dimer is a test used to detect pulmonary emboli.   I often see elevations of this at a time when a pulmonary embolus is thought likely, but scanning reveals nothing.   I believe in these we are looking at a cascade of microemboli into the lungs, which itself produces further inflammatory responses.

 

There are similar implications in cardiovascular disease, as around 2% (or higher as non-coronary heart attacks are not often identified) of patients with heart attacks have no coronary disease.    By and large the mechanism of this is “Takotsubo disease” caused by release of catecholamines.    More likely though, making exact figures impossible to estimate, is that these are occurring in a situation where there is co-existing coronary disease, and the cascade of inflammatory chemicals simply is the straw that breaks the camel’s back.

 

Looking at these processes, you start to question the very fundamental medical theories of hypertension for example, as this is becoming increasingly acknowledged as being “inflammatory.”     An area of research I am involved with is in dilatation of the aortic root and ascending aorta.   These areas, along with the carotid bulb, possess large numbers of baroreceptors, which are part of the body’s blood pressure physiology.   I am very suspicious that this same Takotsubo response is the mechanism for the dilatation, and that this may be as simple as DNA predisposition and likely to be increased after shoulder trauma, or in sportspeople who have had thoracic outlet damage.   There appears to be a significantly high incidence in long distance swimmers, but that at present is subjective only, and more extensive research is required.

 

With awareness of the various “drivers”, patients with fibromyalgia, dysautonomia, migraine and POTS are often able to differentiate the different “drivers” to these patterns of their problems.   For example, someone with popliteal compression may now recognize the paraesthesiae in their hands or feet with posture, and those with mid-thoracic spine injuries especially around T7 can recognize the tachycardia and wave of anxiety with rotation of the spine.   Simply driving with arms outstretched can produce typical symptoms of a panic attack, and weight lifting can produce fatigue, headache and other symptoms.   There is of course a blurring of boundaries, but generally as each driver is worked out, these can be nullified or modified by simple changes- most commonly with diet, posture, lifestyle, targeted pilates programs, and above all, knowledge of the underlying causes.

 

Mast Cell Activation (MCA) provides an easy answer to urticariae when present, but does it answer why IBS is so common?    Perhaps the answer lies in collagen again, with dysfunctional gut linings (where they are affected by mast cell activation as the gut becomes “hyperalert” and tries to expel any food or preservative for example that it perceives as a threat.    This becomes literally the cause of the “Leaky Gut, “with the Mast Cell Activation the mechanism for the sudden onset of things such as anaphylaxis after physical injury.   In a number of auto-immune diseases, diet change alone can control symptoms.   Microflora of the gut has finally become known as a major factor in disease, but this alone does not provide all the answers.      I frequently see parasites especially blastocystis and dientamoeba activating mast cell responses, and managing these can be difficult as blastocystitis is notoriously resistant to traditional management.   The significance of these parasites in disease activation is considered traditionally “controversial” but when the stars are aligned, and the DNA of the sufferer appropriate, disease is activated, while in others, it is of no apparent consequence.

 

Activation by problems such as mould exposure, petrochemicals or toxic products used in our food production is beyond the scope of this article, although strongly acknowledged as potential causes.   When mast cell activation has occurred, people become increasingly hypersensitive- to light, to medication (so even a change of medication to a generic form with different dyes and fillers) to sound, even the smell of venetian blinds.   As I read in this area, MCA has been associated with impaired collagen which in turn affects the gut lining, as well as the other areas of external exposure eg lungs, mouth, vagina, bladder, but this may be part of the issue, as the underlying genetic fault for example is in the MTHFR mutation in migraine has long been associated with collagen issues such as Dupuyrtrens contracture.   So which is the cart and which is the horse?   Or do you need both to tango?

 

I think those of us with issues such as IBS/food intolerance were born with a genetic reduced (sometimes complete) ability to tolerate certain foods, usually cow milk being the first.   This is seen in things like eczema, recurring tonsillitis, colic- and for most by about the age of 2 our developing immune systems are sufficiently developed so we are able to cope with it.    Then there may be some trauma, or parasite etc which triggers off the immune system, and I suspect that is where the MCA comes in to play, and we start to show other symptoms.

 

When collagen is “dysfunctional” it changes its texture, so logically it explains many of those little niggly things that people get, including carpal tunnel, trigger fingers, Peyronie’s disease in men, and I think it is highly likely this carries through to cyst and polyp formation- wherever you like in the body, maybe varicose veins, and highly likely, endometriosis and PCOS.

 

Working with POTS I have seen cardiomyopathy caused by simply lifting arms when the outlet is involved and the subclavian veins blocked.   We have NO data on this as yet, whether it is the compression of the vein itself, or microemboli released after the vein is compressed and the vein distal to the compression dilates and fills, or possibly both.   Hopefully Ross Sharpe’s current research on POPVC and inflammatory responses will give us the answers.    The mechanism in the cardiomyopathy appears to be similar to that in Takotsubo Cardiomyopathy, thought to be a sudden release of cascades of catecholamines.   And the catecholamines are vital to understanding anything at all in the processes.

 

Having variable arthritis- wherever, suggests a dietary cause.    Having positive antibodies to the thyroid (Hashimotos thyroiditis) implicates an inflammatory and usually and at least partly a dietary cause.    The trick is to find the culprits.     Everyone is off doing gluten and dairy free diets, but most I believe are wrong, and coeliac disease no different to any other auto-immune disease.   It may be cow milk, as this is the first “toxic” chemical the body is exposed to in life, but after that there are many possible.    Research in 1999 by Dr David Freed showed the deadly nightshades, the lectins to be triggers to a wide range of auto-immune disease.   But everyone has different triggers, so I urge anyone with evidence of auto-immune disease to at least trial for a week off all lectins and then start adding normal foods and let your body tell you what it doesn’t like.    This is not rocket science.   And then the basis diet we should all be following is as if you lived on an island off Crete.

 

Migraine and PFO

 

When a patent foramen ovale (PFO) is present between the atria of the heart, microemboli from the vascular compression syndromes  shunting through this into the brain may be responsible for cerebral damage particularly dementia, certainly the “stroke-like” symptoms that affect some migraine sufferers.   In the brain MRI, migraine sufferers may have white spots, FLAIR hyperintensities.   Often labelled as small vessel disease, they can also reflect microembolic damage from the compression syndromes, but can also reflect “vasospasm” from the inflammatory chemicals (without a PFO.)    Current unpublished research suggests 60% of severe migraine with aura have associated popliteal compression.   Unfortunately the current level of radiology does not allow us the ability to differentiate between these, so you have to look for other clues.   For example, retinal photography provides an answer to whether there is small vessel disease as in the retina, you actually see the vessels themselves.  Unexplained lung damage including emphysema, pulmonary hypertension and fibrosis are probably associated with this microembolic phenomenon.

 

A brain MRI can reveal a lot, especially if there are no FLAIRs.    Sometimes there are subtle changes that look to indicated the effect of the inflammatory cascade, and these are usually found in people where the cognitive changes in the migraines are severe.

 

Thoracic Compression

 

There are no population studies looking at the incidence of thoracic compression in the community, and it does appear to be far more extensive than I could have even imagined.   It is probably involved in frozen shoulder (adhesive capsulitis) through autonomic responses, and it is possible as a cause of unexplained depression and anxiety.   Among the worst affected people with POTS are the ones with shoulder injuries so it may be a factor in depression in occupations such as football, or servicemen.  This area is the subject of current studies.

 

I can find no incidence studies in syncope in people in public transport who travel with arms up holding straps, but I think we will find it there.   Many of the POTS patients reported pins and needles (paraesthesiae) in their hands/ arms driving or lifting forward, and there was often unexpected fatigue and sometimes shortness of breath with elevated arms, or arms down carrying weights (eg shopping or wheelbarrow use)- and this has been clearly shown in this study, including panic attacks driving with outstretched arms.  As this reflects thoracic compression- caused inflammatory responses, it may suggest a possible cause for driver fatigue, and just may be a contributor in post-natal depression with changes from the pregnancy, then repetitive lifting of increasingly heavy babies.   It certainly warrants a close look.   Similar findings were found from popliteal compression, with simply standing in a line for long periods, or sitting watching TV with knees straight and legs extended provoking headaches, anxiety, neuropathic symptoms, hypersensitivity to sound and light, sleep disruption etc.

 

Shoulder pain is just so common, often not improved and even worse with our normal shoulder treatments, but retracing the injuries there is often a thread implicating an injury to the thoracic outlet rather than the shoulder itself, and as the rotator cuff wears anyway, this ends up as a diagnosis as scans show worn rotator cuffs, so the real problem is missed, and it becomes a treatment failure.

 

During the POTS study, it was trauma to the neck and shoulders that appeared to provoke the most significant symptoms in patients.   The spine is a major factor in triggering TLRs in all the problems of POTS, dysautonomia, migraine and fibromyalgia.   This is obvious in trauma especially MVAs, but it also can be occupational, for example in hairdressers, dentists, nurses and supermarket cashiers, or in people working on computers.    Increasingly symptoms, including mood disorders can be provoked with the increasing use of smart phones, hand held computers and tablets.   Posture is becoming an increasing problem with these devices, and I anticipate increasing problems with spine-driven problems in the future.

 

Treatment

 

The treatment of POTS and all these inflammatory problems should be aimed at removing the driving factors rather than looking for a medication to control symptoms.   Of course if your thyroid is destroyed and not functioning, you will need Thyroxine replacement, or in vascular disease the statins Crestor and Lipitor do have anti-inflammatory effects in the vessels, reducing plaque (forget the word cholesterol), the ARB blood pressure medications probably repair the DNA in damaged vessels, and aspirin reduces cancer risk with its anti-inflammatory actions as well as known anti-stroke and infarct risk.  In MCAS, medication to de-activate the aberrant mast cell response may be needed.   The boundaries are blurring in management as well.

 

At the end it is at its core quite simple – a detailed timeline to look at where activation has occurred, often in early childhood, then work out the drivers, especially in the spine and vascular compression, sort out dietary triggers, look at lifestyle, posture, occupation, supplement where necessary (but as a general rule, you can’t supplement your way out of the symptoms,) and heal what has been damaged, if this is possible.   For patients with FMS and POTS, it is as though they have been caught in a dam that has suddenly broken and they are treading water with heads just above the water.   We as clinicians have to turn off the taps that are letting more water in.   Acupuncture, targeted physiotherapy, improved diet lifestyle, occupational and similar changes allow the flood that has enveloped them to slowly dissipate.

 

People with migraine all would appear to have defects in the MTHFR pathway, which looks to be associated with collagen dysfunction.    Dean Watson showed how injuries to the upper cervical spine can provoke migraine, and this area is probably the most common activating site that I see.   It usually responds to “Watson therapy”, but it requires a highly trained practitioner to achieve his.   Migraine can also be triggered by the vascular compression in the shoulders and legs, so why not pelvis as well, for migraine can be quite severe during the menses.  Research is certainly needed here.

 

 

High-level acupuncture is invaluable in reducing autonomic and inflammatory responses in POTS and FMS while causes are chased.  There are a few physiotherapists sufficiently skilled to work out the spine and thoracic drivers, but these therapists deal with the mechanical causes.   Generic pilates and exercise programs often do more harm than good. There are even fewer dieticians capable of sorting out the food intolerance drivers when present, but they are around.  At present, the research continues, but the knowledge that the popliteal compression can usually be managed by positional change, and the thoracic outlet by awareness, simple shrugging exercises which opens the compressed thoracic outlet, and improved by suitably trained physiotherapists should provide a useful start for clinicians, while looking at other drivers in each patient.

 

Conclusion

 

This POTS study implied that searching for causes and drivers to POTS, migraine, fibromyalgia and similar problems enables better management opportunities that trying to add drugs, or supplements.  This is an evolving science, and I have no doubt further research will unlock even more causes, or at least provide definitive explanations for it all.  It also suggested that there is probably an underlying collagen dysfunction, which may have implications for patients with the leaky gut symptoms of IBS, as well as the current trends towards microflora and Mast cell Activation.

 

Associated with all of this I think we will need to have a good look at the real cause of diseases such as diabetes, hypertension, cardiomyopathy, COPD, vascular disease and auto-immune disease just to name a few.   Anything where there is the word “idiopathic” is a good place to start.  To simply look at an elevated cholesterol (unless you have one of the genetically-driven lipid profile abnormalities,) and say that this causes vascular disease is pure nonsense.    These are all inflammatory processes with multiple causes, most importantly genetic, and it is injury, lifestyle and similar factors which steers you into whatever disease you may develop, dependent on your individual DNA.

 

The work I am doing which is based on current and recent research, much of it at the universities at the Gold Coast and by individual researchers.   There are no Cochrane Guidelines here, as it is an evolving management process, so little has been formally adopted in conventional medicine.

 

References:

  1. Krystel-Whittemore, M., Dileepan, K., Wood, J.G.. Mast Cell: A Multi-Functional Master Cell, 2016. https://www.frontiersin.org/articles/10.3389/fimmu.2015.00620/full
  1. Seneviratne,S.L., Maitland, A., Afrin A.: Mast Cell Disorders in Ehlers-Danlos Syndrome. 2017, American Journal of Medical Genetics Part C, 175C: 226- 236
  1. Mikita, n., Inaba, Y.,Yoshimasu, T., Kanazawa, N., Furukawa, F.: Mast Cells in Collagen Diseases. 2017. https://www.researchgate.net/publication/319359864_Mast_cells_in_collagen_diseases
  1. Bot, I., Shi, G., Kovanen, P.,Mast Cells as Effectors in Atherosclerosis. 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304944/
  1. Afrin, L. Presentation,Diagnosis and Management of Mast Cell Activation Syndrome. 2013. Nova Science Publishers,Inc.
  1. Wikipedia. https://en.wikipedia.org/wiki/File:Allergy_degranulation_processes_01.svg

 

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