Hi Friend
In Part 1 I introduced you to mast cells and why MCAS is so consistently missed. In Part 2 I explained the triad — MCAS, POTS, and hEDS — and why treating any one of these conditions without addressing the others will always leave you falling short.
Today we get into the part that frustrates patients most.
You have been to your GP. You have probably been to A&E during a bad episode. You may have seen a gastroenterologist, a cardiologist, a rheumatologist, a neurologist. You have had blood tests, maybe lots of them. And everything, or almost everything, has come back normal.
And yet you are anything but normal. You are exhausted, reactive, in pain, and increasingly convinced that something is genuinely wrong with you — while the system keeps telling you otherwise.
Here is why that happens, and what good diagnosis actually looks like.
Why Standard Blood Tests Miss MCAS Almost Every Time
Mast cells release their mediators in bursts. They degranulate — the technical term for the release event — episodically, triggered by stimuli, and then the mediators circulate briefly before being metabolised and cleared. The window in which any given mediator is detectable in the blood or urine is often measured in minutes to hours, not days.
A full blood count run on a Tuesday morning when you happen to be in a relatively stable period tells you almost nothing about what your mast cells are doing when you eat, when you stand up, when you are stressed, when the temperature changes, or when you encounter a trigger.
This is not a failure of the test. It is a fundamental mismatch between what the test measures and what the condition does.
There are more specific tests. Serum tryptase is the most widely used — it is a mast cell mediator with a longer half-life and is the standard marker for anaphylaxis. A significantly elevated baseline tryptase is meaningful. But the majority of MCAS patients have a normal or only modestly elevated baseline tryptase. The condition does not require a raised tryptase for diagnosis, and a normal tryptase does not rule it out.
More useful are 24-hour urine tests measuring prostaglandins, particularly prostaglandin D2 and its metabolite 11-beta-prostaglandin F2 alpha, along with N-methylhistamine and leukotriene E4. These capture mediator production over a full day rather than a single snapshot moment, and they should ideally be collected on a symptomatic day, not during a calm period. Even these tests have significant false negative rates, and many specialist labs vary in how reliably they process them.
The honest clinical reality is that MCAS cannot be diagnosed or excluded by a blood test alone. Anyone telling you otherwise does not fully understand the condition.
What Good Diagnosis Actually Looks Like
The diagnostic approach I use with patients at Mend Clinic is built around three pillars working together, not any single test in isolation.
The first pillar is a thorough clinical history. Mast cell disease has a characteristic pattern. Symptoms affecting multiple organ systems simultaneously. Reactions that seem disproportionate or inexplicable. A list of triggers that looks almost random to an outsider but makes biological sense once you understand mast cell behaviour. Episodes that fluctuate — good weeks and bad weeks — without obvious explanation. A personal or family history that may include atopy, food intolerances, unexplained fainting, joint hypermobility, or chronic pain syndromes. The history alone, taken carefully, is remarkably powerful.
The second pillar is appropriate investigation. Not a fishing expedition of random tests, but targeted testing that addresses the biological mechanisms in question. Tryptase, urine mediators on a symptomatic day, relevant allergy panels where indicated, investigation for POTS with a lying and standing heart rate assessment or formal tilt table testing where available, and screening for the connective tissue features of hEDS. Where relevant, thyroid function, inflammatory markers, and immune panels help exclude differentials and identify co-existing conditions.
The third pillar — and this is the one that is most underused and most powerful — is the therapeutic trial.
Treatment Response As Diagnosis
In conditions where testing is inherently imperfect, how a patient responds to targeted treatment is itself diagnostic information of the highest order.
MCAS has a relatively predictable treatment ladder. First-line antihistamines: H1 blockers such as cetirizine or loratadine, combined with H2 blockers such as famotidine to address the histamine receptors in the gut. Mast cell stabilisers such as sodium cromoglicate, quercetin, or ketotifen. Addressing specific mediator pathways with montelukast for the leukotriene component. And dietary modification to reduce exogenous histamine load while the mast cells are being stabilised.
If a patient with a compelling clinical history begins a structured antihistamine and mast cell stabiliser protocol and their symptoms substantially improve — the reactivity reduces, the fatigue lifts, the gut settles, the brain fog clears — that treatment response is confirmatory. It tells you something real about the biology, more reliably in many cases than a urine test run on the wrong day.
This is not unusual in medicine. We diagnose and confirm asthma partly by demonstrating reversibility with a bronchodilator. We confirm coeliac disease partly by watching what happens when gluten is removed. Treatment response is a legitimate and rigorous diagnostic tool when used thoughtfully.
It also means that waiting years for a confirmed laboratory diagnosis before beginning any treatment is not in your best interest. A careful, structured, supervised therapeutic trial can simultaneously help you feel better and provide meaningful diagnostic clarity.
The Problem With The Current System
The NHS pathway for complex chronic illness of this kind is genuinely broken, and I say that not as a criticism of individual clinicians but as a structural reality.
You are referred to gastroenterology for the gut symptoms. They scope you, find nothing, and discharge you. You are referred to cardiology for the palpitations. They do an echo and a Holter, find nothing actionable, and discharge you. You are referred to neurology for the brain fog and pins and needles. They do an MRI, find nothing, and discharge you. Each specialist sees their slice of the picture, finds nothing wrong within their slice, and sends you back.
Nobody is looking at the whole picture. Nobody is asking why a thirty-four year old woman is simultaneously having gut problems, cardiovascular symptoms, neurological symptoms, joint pain, skin reactions, and crushing fatigue. Nobody is connecting the dots.
This is exactly the gap that specialist integrated care for the triad addresses. Not four separate referrals producing four normal results. One clinician, one framework, one coherent treatment plan that treats you as a connected biological system rather than a collection of isolated symptoms.
What To Do If You Recognise This Picture
If you are reading this and recognising yourself — the years of normal tests, the specialists who found nothing, the labels that never quite fit, the sense that your body is reacting to the world in a way nobody can explain — here is what I would suggest.
Start tracking. A detailed symptom diary that captures not just what symptoms you have but when they occur, what preceded them, what you ate, how you slept, your activity level, and any pattern you can identify. This kind of structured history is enormously valuable to any clinician attempting to assess you properly.
Be systematic about potential triggers. Common mast cell triggers include heat, cold, exercise, emotional stress, certain foods particularly those high in histamine or that are histamine liberators, fragrances, alcohol, and hormonal fluctuations. You will likely not react to all of these, but identifying your personal trigger pattern is clinically useful.
Push for appropriate investigation. If you have a clinician willing to engage, ask specifically for serum tryptase, 24-hour urine mediators on a symptomatic day, and a lying and standing heart rate assessment. These are the starting points.
And seek out clinicians who understand the full picture. There are not many of us, but we exist.
Something I Am Building For You
I have been working on something I am genuinely excited about, and I want to give you a first look before I launch it publicly.
Over the past year the single most common message I receive is some version of the same question: I think I might have MCAS. How do I know if my symptoms fit? Where do I even start?
The problem is that a full clinical assessment with me is not accessible to everyone. The waiting time, the cost, the logistics — for many of you, especially those of you outside the UK, that pathway is not straightforward.
So I have been building a new service. A detailed, structured async clinical opinion — meaning you complete a thorough symptom questionnaire, submit your history and any existing test results, and receive back a comprehensive written clinical report from me personally, reviewed against my own diagnostic framework, with a clear assessment of whether your symptom profile is consistent with MCAS, POTS, or hEDS, and a structured set of recommendations for next steps.
Not a chatbot. Not an automated response. A real clinical opinion, in writing, from a specialist who has spent years working with this exact patient population.
This is designed to be the thing that gives you clarity when the system has given you nothing but confusion. A clear, honest, expert assessment of your picture — so you know what you are dealing with, what to ask for, and where to go next.
I am putting the finishing touches on this now. If you want to be among the first to access it when it launches, reply to this email with the word READY and I will make sure you hear about it before it goes anywhere else.
Coming Up In Part 4
Next week we go into treatment in detail. The full MCAS treatment ladder from first-line antihistamines through to mast cell stabilisers, dietary strategies, and the management of POTS alongside MCAS. The practical, clinical, evidence-based guide to actually getting better — not just understanding what is wrong.
Stay well,
This newsletter is for informational purposes only and does not constitute medical advice. If you have concerns about your health, please consult a qualified healthcare professional.
