How can I differentiate histamine‑mediated allergic angioedema, bradykinin‑mediated angiotensin‑converting enzyme (ACE) inhibitor (or neprilysin inhibitor) induced angioedema, and hereditary or acquired C1‑esterase‑inhibitor deficiency angioedema?

Differentiating Angioedema Subtypes

The key to differentiating angioedema is the presence or absence of urticaria: histamine-mediated angioedema typically presents with urticaria and pruritus, whereas bradykinin-mediated angioedema (ACE inhibitor-induced and C1-esterase inhibitor deficiency) presents without urticaria or itching. 1, 2

Clinical Presentation Patterns

Histamine-Mediated Allergic Angioedema

• Presents with concomitant urticaria (hives) or pruritus in most cases 1, 3
• Responds to antihistamines, corticosteroids, and epinephrine 4, 5
• Often associated with identifiable triggers (foods, drugs, insect stings) 4
• Swelling develops rapidly and resolves within hours to days with treatment 4
• May be part of a generalized anaphylactic reaction 4

ACE Inhibitor (or Neprilysin Inhibitor) Induced Angioedema

• Characterized by asymmetric, non-pitting swelling WITHOUT urticaria or pruritus 2, 6
• Prominently involves face, lips, tongue, pharynx, and larynx 6, 7
• Can affect extremities, bowel, or isolated laryngeal structures 2, 7
• Does NOT respond to epinephrine, antihistamines, or corticosteroids 2, 6
• Timing is unpredictable: 60% occur within first month of therapy, but can develop after many years of continuous use 6, 7
• Laboratory studies are normal (normal C1-INH function, normal C4, normal C1q) 3
• Mechanism is bradykinin-mediated due to impaired degradation of bradykinin 6, 4

Hereditary or Acquired C1-Esterase Inhibitor Deficiency Angioedema

Clinical Features Common to Both

• Recurrent episodes of angioedema WITHOUT urticaria 1
• Involves extremities, abdomen, genitourinary tract, face, oropharynx, or larynx 1
• Attacks follow stereotypical pattern: worsen over 24 hours, peak, then slowly resolve over 48 hours 1
• May be preceded by prodrome 1
• Do NOT respond to epinephrine, corticosteroids, or antihistamines 1
• Bradykinin is the primary mediator 1, 4

Hereditary Angioedema (HAE) Specific Features

• Onset typically begins during childhood and frequently worsens around puberty 1
• Positive family history in most patients (autosomal dominant inheritance) 1
• Laboratory diagnosis:
  • Type I HAE: Low C1-INH antigenic AND functional levels, decreased C4, normal C1q 1
  • Type II HAE: Normal C1-INH antigenic levels but decreased C1-INH functional levels, decreased C4, normal C1q 1
• Precipitating factors often unknown, though stress and trauma are recognized triggers 1

Acquired C1-INH Deficiency Specific Features

• Clinical presentation similar to HAE attacks 1
• Laboratory diagnosis: Reduced C1-INH function, activation of complement, and reduced antigenic levels of C1 (low C1q distinguishes from HAE) 1
• Results from enhanced catabolism of C1-INH 1
• May be associated with C1-INH autoantibodies, with or without underlying lymphoma or autoimmune disease 1, 3
• Typically presents in adulthood without family history 3

Diagnostic Algorithm

Step 1: Assess for Urticaria/Pruritus

• If urticaria or pruritus present → Consider histamine-mediated angioedema 1, 3
• If NO urticaria or pruritus → Consider bradykinin-mediated angioedema 1, 2

Step 2: Medication History

• If patient taking ACE inhibitor or ARB → ACE inhibitor-induced angioedema is likely 1, 2
• If patient taking neprilysin inhibitor → Bradykinin-mediated angioedema 6
• Note: ACE inhibitor angioedema can occur even after years of therapy 6, 7

Step 3: Laboratory Testing (for non-urticarial angioedema without ACE inhibitor use)

• Measure C4 level first (screening test):

  • If C4 low → Proceed to C1-INH testing 1
  • If C4 normal → Consider idiopathic angioedema or HAE type III 3

• If C4 low, measure C1-INH antigenic and functional levels plus C1q:

  • Low C1-INH antigenic + low C1-INH functional + low C4 + normal C1q = HAE Type I 1
  • Normal C1-INH antigenic + low C1-INH functional + low C4 + normal C1q = HAE Type II 1
  • Low C1-INH functional + low C4 + LOW C1q = Acquired C1-INH deficiency 1

Step 4: Family and Age History

• Positive family history + childhood onset → HAE 1
• No family history + adult onset → Consider acquired C1-INH deficiency or ACE inhibitor effect 1, 3

Critical Pitfalls to Avoid

• Do not treat bradykinin-mediated angioedema with antihistamines, corticosteroids, or epinephrine alone—these are ineffective 1, 2, 6
• If a patient on an ACE inhibitor presents with angioedema AND urticaria, this suggests alternative diagnosis (histamine-mediated), not typical ACE inhibitor effect 2
• ACE inhibitor angioedema can continue for at least 6 weeks after drug discontinuation 2, 7
• Fresh frozen plasma may acutely exacerbate some HAE attacks despite often being effective 1
• Laryngeal involvement in bradykinin-mediated angioedema is life-threatening and requires immediate airway management 2, 6