What are the causes of Angioedema (Angioneurotic Edema)?

From the Guidelines

Angioneurotic edema is caused by several distinct mechanisms, including hereditary angioedema due to C1 esterase inhibitor deficiency, acquired angioedema from autoimmune disorders or medications, and allergic reactions to foods, medications, or environmental allergens, as well as physical triggers and infections. The most common causes of angioedema include allergic reactions to foods, medications (particularly ACE inhibitors, NSAIDs, and antibiotics), and environmental allergens which trigger histamine release 1. Hereditary angioedema results from C1 esterase inhibitor deficiency, a genetic condition that allows uncontrolled activation of the complement system, leading to increased bradykinin signaling and vascular permeability 1. Acquired angioedema can develop from autoimmune disorders, certain cancers, or medications that interfere with bradykinin metabolism, such as ACE inhibitors, which can cause angioedema in approximately 0.1% to 0.7% of patients 1.

Some key points to consider in the diagnosis and management of angioedema include:

• Hereditary angioedema is characterized by recurrent episodes of angioedema, often with a family history of the condition, and can be diagnosed by measuring C4 and C1INH levels 1.
• Acquired angioedema can be caused by medications, autoimmune disorders, or other underlying conditions, and diagnosis involves demonstration of reduced C1INH function and activation of complement 1.
• Allergic reactions to foods, medications, or environmental allergens can trigger histamine release and cause angioedema, and diagnosis involves identifying the underlying trigger and managing symptoms with antihistamines or other treatments 1.
• Physical triggers like pressure, vibration, or temperature changes may induce angioedema in some individuals, and diagnosis involves identifying the underlying trigger and managing symptoms with avoidance of triggers or other treatments 1.
• Infections, particularly upper respiratory infections, can also precipitate episodes of angioedema through immune system activation, and diagnosis involves identifying the underlying infection and managing symptoms with antibiotics or other treatments 1.

The most recent and highest quality study on this topic is from 2025, which discusses the interplay between on-demand treatment trials for hereditary angioedema and treatment guidelines, highlighting the importance of prompt identification of triggers and effective management of symptoms to prevent recurrent episodes 1. Overall, prompt identification of triggers and effective management of symptoms are essential for preventing recurrent episodes of angioedema and improving quality of life for affected individuals.

From the FDA Drug Label

Hereditary angioedema (HAE) is a rare genetic disorder caused by mutations to C1-esterase-inhibitor (C1-INH) located on Chromosome 11q and inherited as an autosomal dominant trait. The kallikrein-kinin system is a complex proteolytic cascade involved in the initiation of both inflammatory and coagulation pathways One critical aspect of this pathway is the conversion of High Molecular Weight (HMW) kininogen to bradykinin by the protease plasma kallikrein. In HAE, normal regulation of plasma kallikrein activity and the classical complement cascade is therefore not present. During attacks, unregulated activity of plasma kallikrein results in excessive bradykinin generation Bradykinin is a vasodilator which is thought by some to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain.

The causes of angioneurotic edema, also known as Hereditary Angioedema (HAE), include:

• Genetic mutations: Mutations to C1-esterase-inhibitor (C1-INH) located on Chromosome 11q, inherited as an autosomal dominant trait 2.
• Unregulated plasma kallikrein activity: Leading to excessive bradykinin generation, which is thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain 2.
• Dysregulation of the kallikrein-kinin system: A complex proteolytic cascade involved in the initiation of both inflammatory and coagulation pathways 2.

From the Research

Causes of Angioneurotic Edema

• Angiotensin-converting enzyme (ACE) inhibitors are a common cause of angioedema, with an incidence of 0.7% to 1% of patients taking these medications 3, 4, 5.
• The reaction is thought to be mediated by a buildup of bradykinin and does not typically respond to epinephrine, corticosteroids, or antihistamines 3, 6, 5.
• Hereditary and acquired forms of angioedema are also recognized, with quantitative and qualitative measurements of C1 inhibitors important for differentiating between these forms 6.
• Other potential causes of angioedema include allergic reactions, although ACE inhibitor-induced angioedema is a nonallergic reaction 7.

Pathophysiology

• The kallikrein-kinin system is thought to play a major role in the development of ACE inhibitor-induced angioedema, with excess bradykinin production contributing to the reaction 5, 7.
• The renin-angiotensin-aldosterone system is also involved in the complex interplay leading to angioedema 5.

Treatment

• Traditional therapies such as corticosteroids and antihistamines are often ineffective in treating ACE inhibitor-induced angioedema due to its nonallergic nature 3, 6, 5.
• Fresh frozen plasma, C1 esterase inhibitor concentrate, and icatibant have been used successfully in some cases to manage ACE inhibitor-induced angioedema 4, 5.