What causes angioedema?

Causes of Angioedema

Angioedema results from two primary mechanisms: mast cell-mediated histamine release or bradykinin-driven vascular permeability, with the key distinguishing feature being the presence or absence of urticaria (hives). 1

Mast Cell-Mediated Angioedema (Usually with Urticaria)

Type I Hypersensitivity Reactions:

• IgE-mediated allergic reactions to foods (especially eggs, shellfish, nuts), medications, or insect stings (particularly bee and wasp stings) cause acute angioedema typically accompanied by urticaria 1, 2
• These reactions involve antigen binding to specific IgE on mast cells, triggering histamine release 1

Chronic Urticaria-Associated Angioedema:

• Approximately 40% of chronic urticaria patients develop angioedema, with about 10% presenting with angioedema alone 1
• An autoimmune mechanism exists in roughly half of these cases, involving IgG antibodies directed against the IgE receptor (40%) or IgE itself (5-10%) 3

NSAID-Induced Angioedema:

• Cyclooxygenase-1 inhibitors can cause angioedema with or without urticaria through leukotriene-mediated mechanisms 1, 3

Bradykinin-Mediated Angioedema (Without Urticaria)

ACE Inhibitor-Induced Angioedema:

• Occurs in 0.1-0.7% of patients taking ACE inhibitors, representing one of the most common drug-induced causes 1
• Results from impaired degradation of bradykinin and substance P, as ACE normally cleaves these peptides 1, 4
• Can occur within the first month (60% of cases) or even after years of continuous therapy 4
• African Americans face substantially higher risk, as do smokers, older individuals, and females; diabetic patients have lower risk 1, 4

Other Kininase Inhibitor-Associated Angioedema:

• Neprilysin inhibitors and dipeptidyl peptidase IV (DPP-IV) inhibitors increase angioedema risk, especially when combined with ACE inhibitors 1
• Tissue plasminogen activators can trigger angioedema through bradykinin pathway activation 1
• ARBs cause angioedema less commonly than ACE inhibitors, though the mechanism may also involve bradykinin modulation 1
• Aliskiren (renin inhibitor) carries a 0.4% angioedema risk 1

Hereditary Angioedema with C1 Inhibitor Deficiency (HAE-C1INH):

• Caused by pathogenic variants in SERPING1 gene resulting in reduced functional C1 inhibitor levels 1
• Autosomal dominant inheritance with high penetrance 1
• Leads to dysregulated bradykinin production through uncontrolled kallikrein-kinin system activation 1
• At least 95% of patients have reduced C4 levels even between attacks 5

Hereditary Angioedema with Normal C1 Inhibitor (HAE-nC1INH):

• Eight genes now linked to HAE-nC1INH: F12 (factor XII), PLG (plasminogen), ANGPT1 (angiopoietin-1), KNG1 (kininogen-1), MYOF (myoferlin), HS3ST6 (heparan sulfate glucosamine 3-O-sulfotransferase-6), CPN1 (carboxypeptidase N), and DAB2IP (disabled homolog 2 interacting protein) 1, 5
• Autosomal dominant inheritance with variable penetrance 1
• HAE-FXII and HAE-PLG are clearly bradykinin-mediated; mechanisms for other types remain incompletely understood 1
• Many patients still lack an identified pathogenic variant despite having the clinical syndrome 1

Acquired C1 Inhibitor Deficiency:

• Results from C1 inhibitor depletion by circulating immune complexes or IgG antibodies directed against C1 inhibitor 3
• Associated with lymphoproliferative disorders and autoimmune connective tissue diseases 6

Other Mechanisms

Idiopathic Angioedema:

• Pathogenesis unknown; may be histaminergic (mast cell-mediated) or non-histaminergic 3, 7
• A minority may be associated with the same autoantibodies found in chronic urticaria 3
• Diagnosis of exclusion after ruling out other causes 7

Intrinsic Vascular Endothelial Dysfunction:

• Some forms of angioedema result from direct dysfunction of vascular endothelium independent of mast cell or bradykinin pathways 1

Critical Clinical Pitfalls

Do not assume all angioedema is allergic - the absence of urticaria strongly suggests bradykinin-mediated rather than mast cell-mediated angioedema, which requires completely different treatment approaches 1, 8

Screen for C4 levels in recurrent angioedema without urticaria before assuming drug-related etiology, as this cost-effectively identifies hereditary causes requiring specialized management 5

Recognize that ACE inhibitor angioedema can persist for at least 6 weeks after drug discontinuation, and the propensity for recurrence continues during this period 5, 9

Life-threatening presentations involving laryngeal, tongue, or pharyngeal edema occur most commonly in anaphylactic/anaphylactoid reactions and bradykinin-mediated disorders 3