Diagnosis of Mast Cell Activation Syndrome
The diagnosis of Mast Cell Activation Syndrome presents many challenges.
Firstly, MCAS causes a multitude of symptoms and signs. The commonest are these:
Skin writing (Dermatographia) (76%)
Pain all over the body (Fibromyalgia) (75%)
Near fainting and fainting (71%)
Headache (63%)
Itching/nettle rash (urticaria) (63%)
Tingling (58%)
Nausea/vomiting (57%)
Chills (56%)
Skin swelling that moves around the body (56%)
Eye irritation (53%)
Breathlessness (53%)
Gastrointestinal reflux (50%)
Cognitive dysfunction (49%)
Rashes (49%)
Abdominal pain (48%)
Throat irritation (48%)
Palpitations (47%)
Sweats (47%)
Environmental allergies (40%)
Fever (40%)
Non-anginal pain (40%)
EVEN MORE COMPREHENSIVE LIST:
Constitutional:
Fatigue, malaise, feeling hot/cold, sweats, flushing /pallor, itch, brain fogSkin:
Rashes, migratory/focally persistent patchy macular erythema, pruritus (often diffusely migratory), angioedema, striae, dermatographia, hair thinning /alopecia, brittle nails/longitudinal ridges, poor healingNeurological:
Cognitive dysfunction – memory/concentration, word finding difficulties, headache (esp. migraine), peripheral sensory/motor neuropathy including paraesthesia, tics, tremors (typically resting), chronic inflammatory polyneuropathy, seizures (can be “treatment-refractory”), pseudo-seizures, cataplexy, narcolepsyEyes:
Irritated eyes, increased/decreased lacrimation, conjunctivitis, episodic difficulty focusing, lid tremor/tic, solar sensitivity, infectious/sterile inflammationEars:
Infectious/sterile otitis externa/media, hearing loss/hyperacusis, tinnitus, coryza, congestionMouth:
Pain/irritation/burning, leukoplakia, lichen planus, ulcers, sores, angioedema, dental decay, bad taste, throat tickle/discomfort/irritation/pain, post-nasal dripLymphatic:
Lymph nodes, usually small and often waxing/waning in size/migratory, sometimes asymptomatic but may be tender, left upper quadrant discomfort (likely from release of mediators from splenic mast cells with or without detectable splenomegaly)Cardiovascular:
Presyncope/syncope (patients may have been diagnosed PoTS or neurally mediated syncope. Full syncope is rare), swings of hypertension/hypotension, palpitations/dysautonomia, dysrhythmias, chest discomfort/pain (usually non-anginal in character), coronary and peripheral arterial atherosclerosis/spasm/infarction, (includes Kounis Syndrome – allergic reaction), idiopathic acute or chronic heart failure (e.g., Takotsubo syndrome), aneurysms, haemangioma, arteriovenous malformations, telangiectasias), migratory oedema (often non-dependent and with normal cardiac and renal function)Pulmonary:
Rhinitis, sinusitis, pharyngitis, laryngitis, bronchitis, pneumonitis (often confused with infectious pneumonia), dry cough, SOB (often low-grade, inconstant, “I just can’t catch a deep breath” despite normal pulmonary function tests), wheezing, obstructive sleep apnoea, pulmonary hypertensionGastrointestinal:
Dyspepsia, aerophagia, dysphagia, bloating/gas, pain/inflammation (often migratory) in one or more segments of the GIT (from oesophagitis to proctitis) and/or one or more solid organs (e.g., hepatitis, pancreatitis), queasiness, nausea, vomiting (sometimes “cyclical”), diarrhoea / constipation (often alternating), gastroparesis, malabsorption, gastro-oesophageal reflux disease (often “treatment-refractory”) and inflammatory/irritable bowel syndrome are common pre-existing diagnoses, increased/decreased appetite, early satiety, weight gain/lossGenitourinary:
Inflammation (often migratory) in one or more segments of the GUS ( cystitis, vaginitis,) and/or one or more solid organs (e.g., nephritis, prostatitis), chronic kidney disease, endometriosis, chronic low back pain/flank pain/abdominal pain, hydronephrosis , infertility, erectile dysfunction, decreased libido, miscarriages should prompt consideration of antiphospholipid antibody syndrome potentially due to MCADMusculoskeletal:
Muscle pain, often diffusely migratory (fibromyalgia is a common pre-existing diagnosis), arthropathy (typically migratory), joint laxity/hypermobility (diagnosed with hEDS (Type Ⅲ)), osteoporosis/osteopenia, osteoporosis/osteopenia/osteosclerosis. MCAD-driven musculoskeletal pain not uncommonly is poorly responsive to non-steroidal anti-inflammatory drugs and narcoticsEndocrinological/metabolic:
Abnormal electrolytes (including magnesium) and liver function tests, delayed puberty, dysmenorrhoea, endometriosis, hypothyroidism, hyperthyroidism, dyslipidaemia, hyperferritinaemia, selective vitamin deficienciesHaematological:
“Easy” bruising/bleeding, polycythaemia or anaemia (may be macrocytic, normocytic, or microcytic), leukocytosis or leukopenia, chronic (usually mild) monocytosis or eosinophilia or basophilia, thrombocytosis or thrombocytopenia, arterial and/or venous thromboembolic disease.Immunological:
Type Ⅰ, Ⅱ, Ⅲ and Ⅳ hypersensitivity reactions, increased risk for malignancy, autoimmunity, impaired healing, increased susceptibility to infection, elevated/decreased immunoglobulin; modest monoclonal gammopathy of undetermined significance not uncommon – MGUSPsychiatric:
Mood disturbances (e.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, wide variety of sleep disruptionsValidated questionnaires, such as “Diagnosis of Mast Cell Activation Syndrome” are very helpful in making sense of the very varied clinical presentations of MCAS.
Secondly, laboratory diagnosis of Mast Cell Activation Syndrome is not straightforward, as, unlike Systemic Mastocytosis and Cutaneous Mastocytosis, laboratory tests are usually negative, or, at best, borderline. For example, serum tryptase is usually negative in MCAS, in contrast to mastoctyosis. Other tests such as serum Chromogranin A, plasma Heparin, plasma Histamine and 24h urinary Prostaglandin D2 and urinary N-methyhistamine are more useful, but, again, levels are usually borderline.
In 2008 (updated 2017) WHO published guidelines for the diagnosis of mastocytosis, but not MCAS as the presentation of the latter is so variable.
The diagnostic criteria for mastocytosis are simplified as follows:
Major criterion:
Demonstration of excessive numbers of mast cells on biopsy
Minor criteria:
1: Atypical appearance of at least 25% of mast cells on biopsy
2: Expression of CD2 +or- CD25 in blood, marrow or other organs
3: KIT c816V mutation
4: Persistent elevation of serum tryptase
Diagnosis is confirmed by either 1: the major criterion + any minor criterion, or 2: any three minor criteria.
In clinical practice the diagnosis is usually made on demonstration of excessive numbers of mast cells on biopsy and an elevated serum tryptase.
Currently there are two major proposed guidelines for the diagnosis of MCAS – Consensus 1 (first published 2012 and updated 2019) and Consensus 2 (first published 2011 and updated 2017). Other proposals have been published, but do not seem to have as wide acceptance as yet. Each set of guidelines has its strengths and weaknesses. This diversity clearly demonstrates the difficulty in reaching global guidelines for a multisystem condition with an extremely wide range of symptom presentation.
We currently use the updated Consensus 2 proposed guidelines which are listed below in simplified form:
Consensus 2 criteria, in simplified form, for diagnosis of MCAS:
Major criteria:
1: Constellation of clinical symptoms attributable to increased mast cell activation
Minor criteria:
1: Demonstration of excessive numbers of mast cells on biopsy
2: Expression of CD2 +or- CD25 in blood, marrow or other organs
3: Atypical appearance of at least 25% of mast cells on biopsy
4: Detection of activating mutations in mast cells
5: Evidence (serum, plasma, or urine) of above-normal levels of mast cell mediators including:
- tryptase
- histamine or its metabolites (e.g., N-methylhistamine)
- heparin
- chromogranin A (note potential confounders of cardiac or renal failure, neuroendocrine tumours, recent proton pump inhibitor use, or chronic atrophic gastritis)
- other relatively specific mast cell specific mediators
6: Symptomatic response to inhibitors of mast cell activation
Diagnosis established upon demonstration of the major criterion combined with at least one minor criterion.
In clinical practice it is, therefore, possible to diagnose MCAS on the strength of a typical history, and response to mast cell antagonists such as H1 and H2 antagonists, Mast Cell Stabilisers, Leukotriene antagonists, or other medications used for MCAS. However, demonstration of mast cell activators – usually serum chromogranin A, urinary prostaglandin D2 or urinary N-methylhistamine – adds even greater strength to the diagnosis.
Unfortunately, these tests are not routinely available on the NHS in the UK, though, as serum Chromogranin A is used as a marker for neuroendocrine cancer, some NHS laboratories may permit its measurement in suspected MCAS. Some private laboratories offer serum chromogranin A, urinary prostaglandins and urinary N-methylhistamine.
Demonstration of elevated numbers of mast cells by using CD117 staining of intestinal biopsies further strengthens a diagnosis of MCAS. Sadly, use of CD117 staining for this purpose is not widely available in the UK.
Consequently, most UK physicians use a pragmatic approach to diagnosis of MCAS, taking a very careful and comprehensive medical history, followed by examination. The history often uncovers a vast array of symptoms that the patient has not previously volunteered, as they have been present for so long that they have come to consider them as normal. I am constantly amazed at what this approach uncovers. If MCAS is then suspected, targeted, step by step, treatment is commenced with careful documentation of the responses.
For more information on Mast Cell Activation Syndrome please do not hesitate to get in touch with Dr Deering through our appointments page.
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