What is angioedema?

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What is Angioedema?

Angioedema is intermittent, localized, self-limited swelling of the subcutaneous and/or submucosal tissue caused by increased vascular endothelial permeability. 1

Clinical Presentation

  • Angioedema can involve multiple anatomic sites including the extremities, genitourinary tract, abdomen, face, oropharynx, and larynx. 1

  • It may occur in isolation, accompanied by hives (wheals), or as part of a systemic allergic reaction. 1

  • Symptoms may persist for a few hours or last days, resolving spontaneously or after treatment. 1

  • Angioedema can occur at any age, developing spontaneously or in response to a triggering factor. 1

  • The swelling is nonpitting and involves deeper layers than urticaria, which affects only superficial skin. 2

Underlying Mechanisms

The proximate cause of all angioedema is increased vascular endothelial permeability, but the underlying mechanisms differ substantially. 1

Mast Cell-Mediated (Histaminergic) Angioedema

  • Mast cell-mediated angioedema results from mediators associated with mast cell activity, including type I hypersensitivity reactions (IgE-mediated), direct mast cell activation, or chronic urticaria. 1

  • This form typically presents with concomitant urticaria and itching. 3

  • It responds promptly to antihistamines, corticosteroids, and epinephrine. 3

  • Approximately 10-20% of patients with chronic urticaria present with angioedema alone, without visible hives. 1, 2

Bradykinin-Mediated Angioedema

  • Bradykinin-mediated angioedema results from excess production of bradykinin due to activation of the kallikrein-kinin system (KKS), direct cleavage of kininogens by non-contact system proteases, or reduced catabolism of bradykinin. 1

  • This form presents without urticaria or pruritus, distinguishing it from histaminergic angioedema. 3

  • It does NOT respond to epinephrine, antihistamines, or corticosteroids. 3

  • Bradykinin-mediated angioedema progresses more slowly over hours, lasting 24-72 hours, whereas histamine-mediated reactions develop within minutes. 4

Hereditary Angioedema (HAE)

  • HAE is characterized by decreased plasma levels or function of C1 inhibitor (C1-INH), recognized for almost 150 years. 1

  • Type I HAE presents with low C1-INH antigenic and functional levels, while Type II HAE presents with normal C1-INH antigenic levels but decreased functional levels. 1

  • HAE is an autosomal dominant disease; approximately 75% of patients have a positive family history, while 25% represent de novo mutations. 1

  • Onset typically begins during childhood, with 50% of patients experiencing symptoms before age 10, and symptoms frequently worsen around puberty. 1

  • HAE attacks typically worsen progressively for 24 hours, then slowly remit over 48-72 hours. 1

  • HAE with normal C1 inhibitor (HAE-nC1INH) has been described over the last two decades, with some cases having proven genetic pathogenic variants (F12, PLG, ANGPT1, KNG1, MYOF, HS3ST6). 1

ACE Inhibitor-Induced Angioedema

  • ACE inhibitor-induced angioedema is characterized by asymmetric, non-pitting swelling without urticaria or itching, most commonly involving the face, lips, tongue, pharynx, and larynx. 3

  • Approximately 60% of episodes occur within the first month of therapy, but onset may be delayed for years. 3

  • The pathophysiology is bradykinin-mediated due to impaired degradation of bradykinin by ACE inhibition. 3

  • This form does not respond to epinephrine, antihistamines, or corticosteroids. 3

  • ACE inhibitor-induced angioedema is responsible for 30-40% of all angioedema cases seen in U.S. emergency departments. 5

Acquired C1 Inhibitor Deficiency

  • Acquired C1-INH deficiency mimics HAE symptoms but is due to circulating anti-idiotypic antibodies leading to C1-INH consumption or inactivation. 2

  • Patients are often diagnosed with underlying malignant, lymphoproliferative, or autoimmune disorders. 2

  • This condition typically presents after age 40 and can be distinguished from HAE by low C1q levels. 4

Other Mechanisms

  • Intrinsic dysfunction of the vascular endothelium can also cause angioedema through mechanisms independent of both mast cells and bradykinin. 1

  • Drug-induced angioedema can occur through various mechanisms in the absence of specific IgE, including NSAIDs, dipeptidyl peptidase IV inhibitors, and neprilysin inhibitors. 1, 4

Life-Threatening Complications

  • Laryngeal involvement in any form of angioedema is life-threatening and can lead to airway obstruction and death. 3

  • Patients with HAE are at risk of serious morbidity and mortality, with laryngeal attacks carrying a 30% historical mortality risk. 1, 4

  • Tracheotomy is indicated when there is swelling of the tongue, larynx, and trachea that threatens airway patency. 6

Diagnostic Importance

The two most critical diagnostic criteria when evaluating angioedema are: (1) whether the mechanism is mast cell-mediated or another cause (especially bradykinin), and (2) whether it is hereditary or acquired. 1

  • Presence or absence of urticaria and pruritus is the single most important clinical feature distinguishing histamine-mediated from bradykinin-mediated angioedema. 3

  • Response to antihistamines effectively excludes hereditary, ACE inhibitor-induced, and other bradykinin-mediated causes. 3

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

2
Research

Angioedema without urticaria: Diagnosis and management.

Allergy and asthma proceedings, 2025

3
Guideline

Differentiating Angioedema Subtypes

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

4
Guideline

Differential Diagnosis and Management of Spontaneous Angioedema Unresponsive to Antihistamines and Steroids

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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