Leukotrienes

Leukotrienes are lipid mediators synthesized from Arachidonic Acid through the 5-lipoxygenase (5-LOX) pathway — the alternative branch to the COX Enzymes pathway that produces Prostaglandins. Mast Cells produce them during the delayed synthesis phase of Degranulation.

The Cysteinyl Leukotrienes

The mast cell-relevant leukotrienes are the cysteinyl leukotrienes: LTC4, LTD4, and LTE4 (each is a sequential metabolite of the previous).

Their effects are dramatic:

• Bronchoconstriction — 100 to 1,000 times more potent than Histamine at constricting airway smooth muscle. This is not a typo. Leukotrienes are the primary mediators of sustained bronchoconstriction in asthma and mast cell reactions.
• Increased vascular permeability — edema, swelling
• Mucus hypersecretion — respiratory and GI
• Eosinophil recruitment — amplifying the inflammatory cascade
• Coronary artery constriction — can contribute to chest pain and cardiac symptoms

Why They Matter in MCAS

When H1 Antihistamines and H2 Antihistamines don’t fully control symptoms — particularly breathing difficulty, persistent swelling, or ongoing flushing — leukotriene-mediated symptoms are a likely explanation. Antihistamines don’t block leukotriene receptors at all. This is why Montelukast (a CysLT1 receptor antagonist) is often added to the treatment regimen.

The Salicylate/NSAID Shunt

When COX Enzymes are inhibited (by Salicylates, aspirin, ibuprofen, naproxen), more arachidonic acid is diverted through the 5-LOX pathway → more leukotriene production. This is why NSAIDs can paradoxically worsen symptoms in mast cell patients. The COX blockade doesn’t reduce overall arachidonic acid metabolism — it redirects it toward the more potent mediator pathway.

Measurement

LTE4 (the terminal metabolite) is measurable in urine and is one of the markers included in comprehensive 24-Hour Urine Testing for mast cell activation.