What is angioedema?

What is Angioedema?

Angioedema is intermittent, localized, self-limited swelling of the subcutaneous and/or submucosal tissue caused by increased vascular endothelial permeability, which can occur with or without hives and may involve the face, tongue, extremities, gastrointestinal tract, or life-threatening laryngeal structures. 1

Core Pathophysiology

The fundamental mechanism underlying all angioedema is enhanced vascular permeability leading to tissue swelling, though the specific mediators vary by type. 1 The two primary pathways are:

• Mast cell-mediated angioedema results from histamine release through type I hypersensitivity reactions, direct mast cell activation, or as part of chronic urticaria. 1
• Bradykinin-mediated angioedema occurs from excess bradykinin production via kallikrein-kinin system activation, direct kininogen cleavage, reduced bradykinin catabolism (as with ACE inhibitors), or intrinsic vascular endothelial dysfunction. 1

Clinical Presentation

Distinguishing Features by Type

The presence or absence of urticaria (hives) and pruritus is the critical first distinguishing feature:

• Histamine-mediated angioedema most often presents with concomitant urticaria and itching, though approximately 20% present with isolated angioedema. 2, 3
• Bradykinin-mediated angioedema characteristically presents without urticaria or pruritus. 2, 4

Anatomic Distribution

Angioedema can involve multiple sites simultaneously: 1

• Face, lips, tongue, and periorbital region (most common)
• Extremities (hands, feet)
• Oropharynx and larynx (life-threatening)
• Gastrointestinal tract (causing abdominal pain that may mimic surgical emergencies)
• Genitals (less frequent)

Temporal Course

• Bradykinin-mediated attacks progress slowly over hours, typically worsen over approximately 24 hours, peak, then resolve slowly over approximately 48 hours. 2
• Histamine-mediated reactions develop within minutes and resolve more rapidly with treatment. 4

Major Categories of Angioedema

Hereditary Angioedema (HAE)

HAE-C1INH (with C1 inhibitor deficiency):

• Autosomal dominant inheritance with high penetrance 4
• Type I (85%): low C1-INH protein levels 1
• Type II (15%): normal/high C1-INH levels but dysfunctional 1
• Median onset in childhood to early adulthood, often worsening around puberty 2, 4
• Positive family history in most cases 2
• Historical mortality risk of 30% from laryngeal attacks if untreated 4

HAE with normal C1 inhibitor (HAE-nC1INH):

• Multiple genetic variants identified (HAE-FXII, HAE-PLG, HAE-ANGPT1, HAE-KNG1, HAE-MYOF, HAE-HS3ST6, HAE-CPN, HAE-DAB2IP) 1
• Females more frequently affected 1
• Commonly involves face, tongue, hands, feet; less frequently gastrointestinal tract 1
• Estrogen exposure often worsens symptoms 1
• Incomplete penetrance and variable expression even within families 1

Acquired Angioedema

Acquired C1-INH deficiency:

• Typically presents after age 40 4
• Associated with B-cell lymphoproliferative disorders, autoimmune disease, or C1-INH autoantibodies 4
• Distinguished from HAE by low C1q levels 2, 4

ACE inhibitor-induced angioedema:

• Asymmetric, non-pitting swelling without urticaria or itching 2, 5
• Approximately 60% occur within first month of therapy, but onset may be delayed for years 2
• Can persist up to 6 weeks after drug discontinuation 2, 5
• African Americans have substantially higher risk 4
• Commonly involves face, lips, tongue, pharynx, larynx; may involve extremities or gastrointestinal tract 2, 5
• Bradykinin-mediated due to impaired bradykinin degradation 2

Idiopathic Angioedema

• Largest category diagnosed when no identifiable etiology exists with normal C1-INH function and no family history 3
• Further classified as histaminergic or nonhistaminergic based on response to high-dose antihistamines 3

Critical Clinical Pitfalls

Treatment response distinguishes angioedema types and is essential for diagnosis:

• Bradykinin-mediated angioedema does NOT respond to epinephrine, antihistamines, corticosteroids, leukotriene-receptor antagonists, or omalizumab. 2, 4, 6
• If a patient on an ACE inhibitor presents with both angioedema AND urticaria, consider an alternative histamine-mediated diagnosis rather than ACE inhibitor-induced angioedema. 2, 5
• Family history may be unreliable due to recall bias, estrangement, adoption, de novo mutations, or variable penetrance—its absence does not exclude HAE. 1, 4
• Fresh-frozen plasma may paradoxically worsen some HAE attacks despite occasional benefit. 2

Life-Threatening Considerations

Laryngeal involvement represents a medical emergency:

• Laryngeal angioedema can cause complete upper airway obstruction and death from asphyxiation. 1, 7
• Airway management takes precedence over all other interventions in laryngeal attacks. 4
• Published reports document deaths from ACE inhibitor-induced laryngeal edema. 5, 7
• Upper airway edema risk is particularly high with dental manipulations, orofacial surgery, endoscopy, and bronchoscopy. 1