Angioedema

Etiology

• Mast cell-mediated (Allergic): IgE-mediated (foods, venom, meds) or direct mast cell degranulation (opiates, NSAIDs).
• Bradykinin-mediated:
  • ACE inhibitors (ACEi): Most common cause in ED. Can occur anytime (days to years after starting). Risk ↑ in Black patients.
  • Hereditary Angioedema (HAE): Autosomal dominant. C1 inhibitor (C1 INH) deficiency or dysfunction. Onset usually in childhood/adolescence.
  • Acquired Angioedema (AAE): Associated with lymphoproliferative disorders (B-cell lymphoma) or autoimmune diseases.

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.

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Clinical Features

• Rapid-onset, non-pitting, asymmetric edema of subQ and submucosal tissues.
• Common sites: Face, lips, tongue, larynx, extremities, genitals.
• GI Tract: Intestinal wall edema causes severe, colicky abdominal pain, N/V, and watery diarrhea (often mimics acute abdomen).
• Key Distinction:
  • Mast cell-mediated: Accompanied by urticaria (hives), pruritus, flushing, bronchospasm, or hypotension.
  • Bradykinin-mediated: NO urticaria, NO pruritus.

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Management

1. Emergency Stabilization (Airway): Monitor strictly. Early intubation if stridor, voice changes, or significant laryngeal/tongue edema. (Surgical airway/cricothyrotomy if intubation fails). c
2. Discontinue offending agent: Stop ACEi immediately (and avoid ARBs, though risk is lower).
3. Targeted Pharmacotherapy:
   • Mast cell-mediated: IM Epinephrine (first-line for anaphylaxis), H1/H2 blockers, systemic glucocorticoids.
   • Bradykinin-mediated (HAE/ACEi):
     • First-line: Icatibant (Bradykinin B2 receptor antagonist) or Ecallantide (Kallikrein inhibitor) or Purified C1 INH concentrate.
     • Second-line: Fresh Frozen Plasma (FFP) if specific agents are unavailable (contains kininase II which breaks down bradykinin).
     • Note: Epi, antihistamines, and steroids are INEFFECTIVE for bradykinin-mediated angioedema.
4. Prophylaxis (for HAE): Danazol (synthetic androgen) or C1 INH concentrate prior to dental work/surgery.