Key Facts

The critical distinction in angioedema is whether it is histamine-mediated (responds to antihistamines/adrenaline) or bradykinin-mediated (does NOT respond to antihistamines; requires specific treatment). Angioedema without urticaria should prompt investigation for HAE or drug causes.

Epidemiology

• Angioedema with urticaria: very common (affects ~40% of CSU patients)
• HAE: rare (~1 in 50,000); autosomal dominant
• ACEi-induced angioedema: ~0.5% of ACEi users; more common in Afro-Caribbean patients

Aetiology

Histamine-mediated: allergic (food, drug, insect venom), idiopathic (often with CSU), physical Bradykinin-mediated: HAE type I (85% — low C1-INH level), HAE type II (15% — normal level, reduced function), HAE type III (rare, normal C1-INH), ACEi-induced

Pathophysiology

• Histamine pathway: mast cell degranulation → histamine → vasodilation + permeability → tissue oedema
• Bradykinin pathway: C1-INH normally inhibits kallikrein and factor XIIa; deficiency → excessive bradykinin production → vascular permeability
• ACEi blocks bradykinin breakdown (ACE = kininase II) → bradykinin accumulates → angioedema

Histamine-Mediated Angioedema

• Usually accompanied by urticaria (wheals)
• Pruritus is common
• Responds to antihistamines/adrenaline
• Lips, eyelids, tongue, hands, feet

Hereditary Angioedema

• Recurrent episodes of non-pruritic swelling (face, limbs, genitalia, abdomen)
• NO associated urticaria
• Abdominal attacks: severe pain, vomiting (can mimic surgical abdomen)
• Laryngeal oedema: life-threatening — ~25% mortality if untreated
• Family history (AD) — but ~25% are de novo mutations
• Onset: usually puberty; worsens with oestrogen (pregnancy, OCP)

ACEi-Induced

• Angioedema without urticaria
• Can occur at any time during ACEi therapy (days to years)
• Usually affects lips, tongue, face
• More common in Afro-Caribbean patients

Red Flags

• Tongue/laryngeal swelling (airway compromise)
• Angioedema without urticaria in young patient (HAE)
• Abdominal pain attacks (HAE abdominal involvement)
• Angioedema on ACEi

Acute

• ABC assessment: airway patency is priority
• Mast cell tryptase: if anaphylaxis suspected (peak at 1–2 hours)

Investigating Cause

• C4 level: screening test for HAE — LOW even between attacks (very sensitive)
• C1-INH level: low in HAE type I
• C1-INH function: low in HAE type II (level may be normal)
• C1q level: normal in HAE; LOW in acquired angioedema (associated with lymphoproliferative disorders)

Drug Review

• ACEi: stop and switch to ARB (lower risk but not zero)
• NSAIDs, aspirin: can cause or worsen angioedema

Additional

• Complement panel (C3, C4): C4 low in HAE
• Family screening: if HAE confirmed — genetic testing available

Acute Allergic/Histamine-Mediated Angioedema

• Airway management: ABC approach; call anaesthetics if airway threatened
• Adrenaline IM 0.5mg (1:1000): if anaphylaxis or severe angioedema
• Chlorphenamine 10mg IV: antihistamine
• Hydrocortisone 200mg IV: prevent biphasic reaction

Acute HAE Attack

• C1-INH concentrate (Berinert) IV: first-line
• Icatibant 30mg SC (bradykinin B2 receptor antagonist): self-administered
• Fresh frozen plasma: if C1-INH concentrate unavailable
• Adrenaline and antihistamines are INEFFECTIVE in HAE
• All HAE patients should carry emergency treatment and have management plan

HAE Prophylaxis

• Long-term: danazol (attenuated androgen — increases C1-INH production); tranexamic acid
• Modern prophylaxis: lanadelumab (anti-kallikrein antibody) SC every 2 weeks; berotralstat (oral kallikrein inhibitor)
• Short-term (pre-procedure): C1-INH concentrate before dental/surgical procedures
• Avoid: oestrogen-containing contraceptives (worsen HAE); ACEi contraindicated

ACEi-Induced Angioedema

• Stop ACEi permanently: switch to ARB (discuss small residual risk)
• Acute: antihistamines ± steroids may help; icatibant in severe cases

Referral Criteria

• Immunology: all suspected HAE for diagnosis and management plan
• A&E: acute airway-threatening angioedema
• Allergy: recurrent angioedema of unclear cause

• Allergic angioedema: excellent with trigger avoidance
• HAE: lifelong condition; modern prophylaxis (lanadelumab) dramatically reduces attack frequency
• HAE laryngeal oedema: ~25% mortality if untreated; near-zero with appropriate emergency treatment
• ACEi-induced: resolves after drug withdrawal (may take weeks)
• Acquired C1-INH deficiency: treat underlying lymphoproliferative disorder

HAE Types

Angioedema: Histamine vs Bradykinin