Angioedema

• Mast cell activation
  • Type 1 hypersensitivity reactions (IgE-mediated)
  • Direct mast cell activation (eg, opioids)
  • Associated pruritus & urticaria
• Excess bradykinin
  • ACE inhibitors
  • C1 inhibitor deficiency (hereditary/acquired)
  • No pruritus or urticaria

Feature	Allergic (Mast Cell)	ACE Inhibitor-Induced	Hereditary Angioedema
Mediator	IgE-mediated type I hypersensitivity $\to$ Mast cell degranulation $\to$ Histamine release	ACE inhibition prevents breakdown of Bradykinin $\to$ Vasodilation & permeability	C1 Esterase Inhibitor Deficiency $\to$ Unchecked activation of Kallikrein $\to$ $\uparrow$ Bradykinin
Key Sx	Urticaria + Pruritus	NO urticaria/pruritus	NO urticaria/pruritus + Abd pain
Dx	Clinical / ↑ Tryptase	Hx of ACE-I use	↓ C4 (Screening), ↓ C1-INH
Acute Tx	Epinephrine (IM)	Stop drug + Airway	C1-INH concentrate or Icatibant
Chronic	Avoid triggers	Switch drug class	Danazol (androgen)

Kallikrein-Kinin System

• Pathway
  • Activation:
    • Factor XIIa (Hageman Factor) converts Prekallikrein → Kallikrein.
  • Bradykinin Generation:
    • Kallikrein cleaves High Molecular Weight (HMW) Kininogen → Bradykinin.
  • Degradation:
    • Bradykinin is degraded by ACE (Angiotensin Converting Enzyme), also known as Kininase II, and C1 esterase inhibitor.
• Bradykinin Effects
  • Vasodilation (via Nitric Oxide & Prostacyclin).
    • ACE can ↑ Angiotensin II and ↓ Bradykinin, both contribute to ↑ Blood Pressure
  • ↑ Permeability (Edema).
    • C1 Esterase Inhibitor can inhibit classical pathway and Kallikrein, both inhibit inflammation.
  • Pain.
• High-Yield Associations
  • ACE Inhibitors: Block degradation → ↑ Bradykinin → Dry Cough & Angioedema.
  • Hereditary Angioedema:
    • Deficiency: C1 Esterase Inhibitor (Autosomal Dominant).
    • Mechanism: Overactive Kallikrein → ↑ Bradykinin.
    • Labs: ↓ C4.
    • Contraindication: Do NOT give ACE Inhibitors.