From the Guidelines
The connection between acetylcholine at nerve endings and mast cell degranulation with histamine release in aquagenic pruritus and aquagenic urticaria is a complex, sequential pathophysiological process involving sensory nerve stimulation and mast cell interaction. This process is triggered when water contacts the skin, leading to the release of acetylcholine from nerve endings, which then promotes mast cell degranulation and histamine release 1. The released histamine amplifies the pruritic response by activating H1 receptors on sensory nerves and contributes to wheal formation in aquagenic urticaria through increased vascular permeability.
Key Pathophysiological Steps
- Acetylcholine release from nerve endings upon water contact
- Sensory nerve stimulation by acetylcholine
- Interaction of acetylcholine with nearby mast cells
- Mast cell degranulation and histamine release
- Histamine activation of H1 receptors on sensory nerves and contribution to wheal formation
Clinical Implications
The understanding of this dual-mediator pathway explains why some patients respond to anticholinergics like scopolamine, while others benefit from antihistamines, as mentioned in guidelines for managing urticaria 1. Temperature changes in water may enhance this process by affecting acetylcholine release and mast cell sensitivity, which is relevant in the context of physical urticarias, including aquagenic urticaria 1.
Treatment Considerations
Given the role of histamine in the pathogenesis of aquagenic urticaria, antihistamines, such as nonsedating H1 antihistamines (e.g., cetirizine, desloratadine, fexofenadine), are considered a primary treatment option 1. The choice of antihistamine and the decision to use them in combination with other treatments, such as anticholinergics, should be based on individual patient responses and the severity of symptoms. Adjustments to the timing of medication and consideration of sedating antihistamines at night may also be beneficial for some patients 1.
From the Research
Connection between Acetylcholine and Mast Cell Degranulation
- The connection between acetylcholine (ACh) at the nerve ending level and mast cell degranulation with histamine release in the pathogenesis of aquagenic pruritus and aquagenic urticaria is supported by several studies 2, 3.
- In aquagenic pruritus, pharmacological studies have shown that the condition is associated with local release of acetylcholine in the skin, mast-cell degranulation, and raised blood histamine concentrations 2.
- The mechanism by which water produces mast cell degranulation and histamine release remains unclear, but it is thought to involve the release of unknown mediators that stimulate dysfunctional and hyper-innervated C-nerve fibers 4.
Role of Acetylcholine and Histamine
- Acetylcholine is thought to play a role in the pathogenesis of aquagenic pruritus, as it is released in the skin upon contact with water and contributes to mast cell degranulation and histamine release 2.
- Histamine is also involved in the pathogenesis of aquagenic pruritus and urticaria, as it is released from mast cells and causes pruritus and other symptoms 5, 3.
Neurological Factors
- Small-fiber neuropathy involving itch/pain-transmitting C-fibers appears to be pathogenetically important in aquagenic pruritus, as patients with the condition have increased intra-epidermal nerve fibers and raised warmth detection threshold 4.
- The use of capsaicin cream, which induces the release of neuropeptides from A delta and C cutaneous nerve fibers, has been shown to be effective in treating aquagenic pruritus, suggesting that neuropeptides may contribute to mediating the itch in the condition 6.