Hypermobile Ehlers-Danlos Syndrome Is Associated with Increased Histamine Through Mast Cell Activation
Yes, hypermobile Ehlers-Danlos syndrome (hEDS) can cause increased histamine levels through its association with Mast Cell Activation Syndrome (MCAS), where mast cells inappropriately degranulate and release histamine along with other inflammatory mediators into surrounding tissues. 1
Mechanism of Histamine Elevation in hEDS
Connective Tissue Dysfunction Triggers Mast Cell Abnormalities
Skin biopsies in hEDS patients demonstrate altered collagen fibril structure that triggers fibroblast dysfunction within connective tissue, affecting cellular adhesion and cytoskeletal responses. 1
The connective tissue in hEDS is softer and less stiff than in control subjects, creating an abnormal microenvironment where mast cells reside. 1, 2
Mast cells migrate into and proliferate within this abnormal connective tissue, where they contain granules of histamine, heparin, and various proinflammatory cytokines. 1
Mast Cell Activation Syndrome (MCAS) in hEDS
MCAS is characterized by abnormal mast cell activation triggered by food, heat, emotion, and mechanical stimuli, leading to early or excessive degranulation without mast cell proliferation. 1
When mast cells degranulate, they release histamine directly into surrounding tissues, affecting multiple organ systems including skin, gastrointestinal tract, respiratory tract, and cardiovascular system. 1
The mechanical stimuli sensitivity is particularly relevant in hEDS, as joint hypermobility and tissue laxity may create repetitive mechanical triggers for mast cell activation. 2
Prevalence of the hEDS-MCAS Association
In a prospective study of 139 patients with MCAS and refractory GI symptoms, 23.7% had EDS, demonstrating a significant association between these conditions. 1
Research suggests that aberrant mast cell activation plays a role in disrupting connective tissue integrity through histamine and tryptase activity, potentially creating a bidirectional relationship between hEDS and MCAS. 3
Some experts propose that certain variants of MCAS may actually drive hEDS pathology, though the exact cellular and molecular linkages remain under investigation. 4
Clinical Manifestations of Elevated Histamine
Multisystem Symptoms
MCAS symptoms typically occur in 2 or more body systems simultaneously, including GI tract, skin, cardiac, and nervous system manifestations. 1
Patients may experience severe skin overreaction to any contact (water, clothes, bed sheets), impressive rash exacerbated after showering (the "shower sign"), fatigue, and headaches. 5
Gastrointestinal Manifestations
Common GI symptoms include abdominal pain (56.1% of patients), nausea (42.3%), constipation (38.6%), heartburn (37.6%), and IBS-like symptoms (27.5%). 6
Over 60% of hEDS patients experience at least one GI symptom, with those having concomitant MCAS being more likely to have fibromyalgia, IBS, GERD, or dysmotility. 1
Diagnostic Approach
When to Test for MCAS
Testing for MCAS should be targeted to patients presenting with clinical manifestations of MCAS (multisystem symptoms triggered by specific stimuli), but universal testing for MCAS in all hEDS patients is not supported by current evidence. 1
Look for symptoms affecting 2 or more organ systems with triggers such as specific foods, temperature changes, strong smells, alcohol, or mechanical stimuli. 1, 2
Diagnostic Criteria for MCAS
Measure serum tryptase levels during symptomatic episodes, looking for an increase from individual baseline to plus 20% + 2 ng/mL. 1
Document response of symptoms to mast cell-stabilizing agents, drugs directed against mast cell mediator production, or drugs blocking mediator release or effects. 1
Note that histamine and histamine metabolites, prostaglandin D2, and leukotriene C4 metabolites have been proposed as markers but are less specific than tryptase. 1
Treatment Approach
Pharmacologic Management
Histamine receptor antagonists (H1 and H2 blockers) are first-line therapy for MCAS-related symptoms in hEDS patients. 2, 5
Mast cell stabilizers provide effective management with minimal side effects for severe MCAS presentations. 5
Treatment should focus on the most prominent symptoms and documented abnormalities rather than empiric therapy. 1, 2
Dietary and Trigger Avoidance
Low-histamine diets may benefit patients with documented MCAS, but should be delivered with appropriate nutritional counseling to avoid restrictive eating patterns. 7, 2
Minimize mechanical stimuli that trigger mast cell activation, particularly in areas of joint hypermobility. 2
Avoid other common triggers including certain foods, alcohol, strong smells, and temperature extremes. 2
Important Clinical Caveats
Not all hEDS patients have MCAS or elevated histamine levels—the association exists but is not universal. 1
The diagnosis of hEDS must be based on 2017 criteria, and MCAS should be categorically established rather than assumed, as the nature and extent of the link between these conditions requires further investigation. 1
Classical EDS and vascular EDS subtypes also show associations with GI manifestations (58.9% and 47.3% respectively), though the MCAS association is most studied in hypermobile type. 6
There is insufficient evidence to support routine mast cell staining on endoscopic biopsies for isolated GI symptoms without evidence of a generalized mast cell disorder. 1