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PMCHS · Comorbidity map

Associated comorbidities
of the PMCHS terrain

A single underlying mechanism — hyperreactive mast cells — can express itself across virtually every system in the body. This map documents the most frequently co-observed conditions.

Strong link — documented in literature
Probable link — converging data
Associated — epidemiological signal
PMCHS is not just another disease: it is a biological terrain that makes the body vulnerable to a wide spectrum of conditions. These comorbidities are not"complications" — they often share the same root mechanism. Recognising this common denominator radically changes the therapeutic approach.
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Neurological & psychiatric
Brain mast cells · neuroinflammation · HPA axis
TDAH / ADHD
Mast cell hyperactivity in the thalamic reticular nucleus → hyperexcitability. Very high co-occurrence in PMCHS families.
Autism (ASD)
Prenatal neuroinflammation, cerebral mast cell activation, gut-brain axis. Consistent maternal transmission ratio.
Fibromyalgia
Central sensitisation, hyperactive cutaneous and muscular mast cells, diffuse pain without identifiable structural lesion.
PTSD / SSPT
Trauma → NR3C1 methylation → dysregulated HPA axis → lowered mast cell threshold. Bidirectional trauma/neuroinflammation loop.
Treatment-resistant depression
Documented neuroinflammatory component. Standard antidepressants remain ineffective without treating the underlying mast cell terrain.
Chronic anxiety
Histamine = wakefulness neurotransmitter. Chronic excess → hypervigilance, insomnia, panic attacks.
Migraine / MAV
Vasoactive histamine → trigeminal → aura. Menstrual migraines: double histamine peak (dietary + hormonal).
ME/CFS (chronic fatigue)
Dysautonomia, mitochondrial dysfunction, chronic immune activation — PMCHS terrain frequently identified.
Idiopathic hypersomnia
Histamine regulates wakefulness via H1/H3. Dysregulation of the histaminergic axis → daytime sleepiness unresolved by sleep.
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Cardiovascular & autonomic
Cardiac mast cells · vasoactive histamine · dysautonomia
POTS
Orthostatic intolerance, postural tachycardia. Often mistaken for anxiety. Cardiac mast cells + dysautonomia + hypermobility.
Kounis syndrome
Coronary spasm or ACS of allergic/mast cell origin. Can mimic myocardial infarction without atherosclerotic lesion.
Unexplained arrhythmias
Cardiac mast cells release histamine and tryptase → conduction disruption. Nocturnal palpitations are common in the PMCHS profile.
Orthostatic hypotension
Peripheral histamine vasodilation + reduced vagal tone (demyelination) → blood pressure drops on standing.
Labile hypertension
Blood pressure fluctuations without identified cause — chronic sympathetic dominance linked to mast cell activation.
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Skin & mucous membranes
Dermal mast cells · local histamine · skin barrier
Chronic spontaneous urticaria
Recurrent dermal mast cell degranulation without identified allergen. Very frequent signal in PMCHS families.
Dermographism
Factitious urticaria triggered by mechanical pressure. Near-pathognomonic sign of cutaneous mast cell hyperreactivity.
Rosacea
Peri-vascular mast cells → histamine and VEGF → erythema, telangiectasias. Hormonal worsening (cycle, menopause) typical of PMCHS terrain.
Hidradenitis suppurativa
Deep follicular inflammation, mast cells activated by TNF-α. Strong link with PCOS and hormono-inflammatory terrain.
Atopic eczema
Skin barrier disruption + IgE-sensitised mast cells. Often the first paediatric sign of the PMCHS terrain.
Psoriasis
Mast cell component documented via IL-17/TNF. Higher co-occurrence than in the general population on PMCHS terrain.
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Gynaecological & hormonal
Uterine mast cells · ERα/GPR30 · oestrogen-histamine loop
Endometriosis
Endometrial mast cells → NGF + VEGF → lesional angiogenesis. Oestrogens amplify degranulation via ERα.
PCOS
Elevated androgens + chronic mast cell inflammation + insulin resistance. Triple pro-inflammatory loop characteristic of PMCHS terrain.
Severe PMS / PMDD
Progesterone drop in luteal phase → release of brake on mast cell activation → premenstrual symptom flare.
Amplified menopause
Oestrogen drop removes the ERβ brake on mast cells → dramatic unveiling of the terrain. Hot flushes are often histaminergic in origin.
Vulvodynia / vestibulodynia
Hyperactive vulvar mast cells → NGF → local nerve sensitisation. Characteristic cyclical worsening.
Recurrent miscarriage
Uterine mast cells involved in foetal immune tolerance. Excessive activation → early rejection. Strong epidemiological signal in PMCHS survey.
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Digestive & intestinal
Intestinal mast cells · permeability · gut-brain axis
SII / IBS
Hyperactive intestinal mucosal mast cells → hyperpermeability + visceral hypersensitivity. Often diagnosed before PMCHS.
Atypical GERD / reflux
Oesophageal mast cells + histamine → lower sphincter relaxation. Resistant to PPIs alone without treating the underlying terrain.
Eosinophilic oesophagitis
Co-activation of mast cells/eosinophils in the oesophageal wall. Chronic unexplained dysphagia in young adults.
SIBO
Dysbiosis linked to mast cell-driven hyperpermeability promotes bacterial overgrowth. Vicious cycle SIBO → bacterial histamine → terrain worsening.
IBD (Crohn's, UC)
Mast cells are key actors in chronic intestinal inflammation. Higher co-occurrence on PMCHS terrain than in the general population.
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Musculoskeletal & connective tissue
Synovial mast cells · collagen · hypermobility
hEDS / SED-H
Documented hEDS / PMCHS / POTS triad. Synovial mast cells degrade collagen via metalloproteinases. Very high co-occurrence.
Lipedema
Adipose mast cells + ERα/GPR30 loop → diet-resistant pathological fatty tissue. Almost universally present in women with PMCHS.
Inflammatory arthritis
Synovial mast cells release TNF-α, IL-6, histamine → chronic joint inflammation. Migratory polyarthralgia is frequent in PMCHS profiles.
Early osteoporosis
Bone mast cells activate osteoclasts via RANKL. Systemic mastocytosis is a recognised cause of osteoporosis — spectrum extended to PMCHS.
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Metabolic & endocrine
Insulin resistance · thyroid · GIH · hypothalamic axis
Refractory obesity
Adipose mast cells → TNF-α + IL-6 → insulin resistance → weight gain independent of caloric intake. Resistance to conventional diets.
Central thyroid dysfunction
GIH: down-regulation of hypothalamic H1 receptors → suboptimal TRH signal → low-normal TSH with clinical hypothyroid signs.
Early type 2 diabetes
Pancreatic mast cell inflammation → beta cell dysfunction. Earlier onset than in the general population on PMCHS terrain.
General interoceptive hypoesthesia (GIH)
Absent thirst, extinguished satiety, fatigue without warning: blindness to internal signals via hypothalamic H1 down-regulation. E. Silva 2026 hypothesis.
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Pulmonary & ENT
Bronchial mast cells · bronchomotor histamine · larynx
Refractory asthma
Non-allergic, unresolved by bronchodilators. Bronchial mast cells release histamine + LTC4 → bronchoconstriction. Montelukast often effective.
Sleep apnea (without obesity)
Laryngeal mast cells + reduced vagal tone (demyelination) → nocturnal obstruction. Lean PMCHS profile with unexplained OSA.
Vasomotor rhinitis
Chronic congestion without documented allergy. Local histamine → mucosal vasodilation. Worsened by histamine-rich foods.
Long COVID
SARS-CoV-2 activates pulmonary mast cells → inflammatory persistence. PMCHS terrain = documented risk factor for long COVID (Afrin et al.).
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Immunoallergic & autoimmune
Immune dysregulation · autoantibodies · multiple intolerances
Multiple intolerances
Histamine, salicylates, sulphites, FODMAPs, fragrances: each molecule lowers the threshold. The cumulative load triggers reactions, not any single substance.
Systemic lupus erythematosus
Mast cells activate auto-reactive plasma cells. Documented in G1-G4 family mapping from PMCHS survey (maternal line).
Hashimoto's thyroiditis
Thyroid mast cells → IL-6 + TNF-α → autoimmune follicular inflammation. Frequently co-diagnosed with PMCHS.
Multiple chemical sensitivity
Mast cell activation threshold so low that minimal exposures (fragrances, detergents) suffice. Often mistakenly perceived as psychosomatic.
Multiple sclerosis
Myelin mast cells → tryptase/chymase → myelin degradation → progressive demyelination. Familial signal documented in PMCHS data.
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Medications that may aggravate the PMCHS terrain
Caution · discuss with your doctor before stopping or changing any treatment
Class Examples Mechanism Risk
Opioids Morphine, codeine, pethidine Direct non-IgE mast cell degranulation High
NSAIDs Ibuprofen, aspirin, ketorolac COX-1 inhibition → shift toward the leukotriene pathway Variable
IV vancomycin Intravenous form only "Red Man Syndrome" — direct histamine release High
Fluoroquinolones Ciprofloxacin, levofloxacin Interference with histamine breakdown (DAO) Moderate
Beta-lactams Amoxicillin and derivatives Documented non-allergic hypersensitivity on mast cell terrain Moderate
ACE inhibitors Lisinopril, enalapril Increased bradykinin → mast cell activation Moderate
Beta-blockers Propranolol, metoprolol Lowers the mast cell activation threshold, hinders epinephrine action in emergencies Moderate
Neuromuscular blockers Atracurium, succinylcholine Histamine release during general anaesthesia High
Ester local anaesthetics Benzocaine, procaine, tetracaine Documented triggers; lidocaine (amide) is generally well tolerated Moderate
Iodinated contrast media Injected imaging contrast Non-IgE mast cell activation upon injection Moderate
PPIs Omeprazole, lansoprazole Possible interference with histamine breakdown (DAO) Variable
Muscle relaxants Some central muscle relaxants Excipients and some molecules reported as triggers Variable
Alcohol (excipients) Oral solutions, syrups Degranulation cofactor in many PMCHS profiles Moderate

This list is not exhaustive and sensitivity varies greatly between individuals — many PMCHS profiles tolerate several medications listed here very well. Never stop an ongoing treatment without medical advice.

📄 Download the full, sourced list

This map is derived from the PMCHS framework (E. Silva, 2026) and international survey data (N=423). It is updated as new references are integrated.
For detailed notes on each comorbidity: refer to the preprints