What is the pathogenesis of urticaria?

Pathogenesis of Urticaria

Urticaria results from mast cell and basophil activation with subsequent release of histamine and other vasoactive mediators, leading to increased vascular permeability of postcapillary venules and development of edema, erythema, and pruritus. 1, 2

Core Pathophysiologic Mechanism

The fundamental process involves degranulation of mast cells and basophils, which can occur through multiple pathways 1, 3:

• Histamine is the primary mediator causing vasodilation, increased vascular permeability, and fluid exudation into surrounding tissues 2, 4
• Additional mediators include leukotrienes, prostaglandins, cytokines, chemokines, and other pro-inflammatory substances that amplify the inflammatory response 3, 4
• These mediators collectively produce the characteristic wheals and angioedema through accumulation of secondary inflammatory cells 3

Immunologic Mechanisms

IgE-Mediated (Type I Hypersensitivity)

• Classic allergic pathway involves IgE antibodies bound to mast cell receptors, triggered by specific allergens (foods, medications, insect stings) 1, 4
• This is the most commonly recognized immunologic mechanism, particularly in acute urticaria 4

Autoimmune Mechanisms (Chronic Urticaria)

Autoantibodies to FcεRI or IgE are responsible for 30-50% of chronic urticaria cases 3:

• Circulating IgG antibodies directed against the high-affinity IgE receptor (FcεRIα) or against IgE itself activate mast cells and basophils 2, 3
• This autoimmune mechanism explains why 40-60% of chronic urticaria patients have functional histamine-releasing autoantibodies 2
• Thyroid autoimmunity is present in 14% of chronic urticaria patients (versus 6% in controls), with elevated antithyroid antibodies even in euthyroid individuals 1, 2

Complement-Mediated Pathway

• Activation of the complement cascade produces anaphylatoxins (C3a, C5a) that directly trigger histamine release from mast cells 1, 4
• This mechanism is particularly relevant in angio-oedema without weals, involving complement activation and bradykinin formation rather than histamine 1

Non-Immunologic Mechanisms

Direct mast cell degranulation can occur independently of IgE receptor activation 1:

• Certain drugs (codeine, opioids) and agents (radiocontrast media) directly trigger mast cell degranulation without requiring IgE 1
• NSAIDs and aspirin cause or aggravate urticaria through uncertain mechanisms, probably involving leukotriene formation and histamine release 1
• Dietary pseudoallergens (salicylates, azo dyes, food preservatives) similarly trigger non-IgE-mediated pathways 1

Bradykinin-Mediated Pathway

• ACE inhibitor-induced angio-oedema results from inhibition of kinin breakdown by ACE, leading to bradykinin accumulation 1
• C1 esterase inhibitor deficiency causes angio-oedema through dysregulated bradykinin formation 1

Intracellular Signaling Dysregulation

Dysregulation of intracellular signaling pathways involving Syk, SHIP-1, or SHIP-2 in basophils and mast cells contributes to chronic urticaria pathogenesis 3:

• These pathways represent non-antibody-mediated mechanisms of mast cell activation
• This understanding has led to development of Syk inhibitors as potential therapeutic targets 3

Physical Urticaria Mechanisms

Physical urticarias involve reproducible triggering by specific stimuli 1:

• Mechanical stimuli (pressure, vibration, dermographism) activate mast cells through direct physical forces
• Thermal stimuli (heat, cold) trigger temperature-sensitive pathways
• Cholinergic urticaria is primarily induced by stimuli for sweating (elevated core temperature, exercise) rather than heat per se 1

Clinical Pitfalls

• Many cases remain idiopathic despite thorough evaluation—80-90% of chronic urticaria has no identifiable cause 5
• The presence of thyroid autoantibodies does not necessarily indicate thyroid dysfunction; patients are typically euthyroid 2
• Associations with occult infections (dental abscess, gastrointestinal candidiasis) have little supporting evidence 1
• Helicobacter pylori shows some association—chronic urticaria resolution is more likely when antibiotic therapy successfully eradicates the infection 1
• No statistical association exists between malignancy and urticaria, despite individual case reports 1