What are the causes of Quincke's disease (angioedema)?

Causes of Quincke's Disease (Angioedema)

Quincke's disease (angioedema) results from two fundamental mechanisms: mast cell-mediated histamine release or bradykinin-driven vascular permeability, with multiple hereditary, acquired, and drug-induced causes that require systematic evaluation to guide treatment. 1

Primary Mechanisms of Angioedema

All forms of angioedema share a common final pathway of increased vascular endothelial permeability leading to tissue swelling, but the upstream mechanisms differ substantially 2:

Mast Cell-Mediated Causes

• Allergic reactions (Type I hypersensitivity) occur when antigens bind to specific IgE on mast cells, triggering histamine release and causing acute angioedema typically accompanied by urticaria 1
• Common allergens include foods (especially eggs, shellfish, nuts), medications, insect stings (bee and wasp venom), and contrast agents 3, 4
• Chronic urticaria causes angioedema in approximately 40% of patients, with about 10% presenting with angioedema alone without hives 1, 4
• Autoimmune mechanisms account for roughly half of chronic urticaria cases, involving IgG antibodies directed against the IgE receptor (40%) or IgE itself (5-10%) 4
• NSAIDs (particularly cyclooxygenase-1 inhibitors) can cause angioedema with or without urticaria through leukotriene-mediated mechanisms 4

Bradykinin-Mediated Causes

Drug-Induced Angioedema:

• ACE inhibitors cause angioedema in 0.1-0.7% of patients through impaired degradation of bradykinin and substance P, representing one of the most common drug-induced causes 1, 2
• ACE inhibitor angioedema occurs most frequently within the first month of therapy but can develop even after many years of continuous use 2
• Risk factors include African American race (substantially higher risk), smoking, increasing age, female sex, while diabetic patients have lower risk 1, 2
• ARBs (angiotensin receptor blockers) cause angioedema less commonly than ACE inhibitors 2
• Neprilysin inhibitors and DPP-IV inhibitors increase angioedema risk, especially when combined with ACE inhibitors 1

Hereditary Angioedema (HAE):

• HAE with C1 inhibitor deficiency (HAE-C1INH) results from pathogenic variants in the SERPING1 gene, causing reduced functional C1 inhibitor levels and dysregulated bradykinin production through uncontrolled kallikrein-kinin system activation 1, 2
• At least 95% of HAE-C1INH patients have reduced C4 levels even between attacks, making this an excellent screening tool 1
• HAE with normal C1 inhibitor (HAE-nC1INH) is linked to pathogenic variants in eight genes: F12, PLG, ANGPT1, KNG1, MYOF, HS3ST6, CPN1, and DAB2IP 1, 2

Acquired C1 Inhibitor Deficiency:

• Results from enhanced catabolism of C1 inhibitor due to circulating immune complexes or IgG antibodies directed against C1 inhibitor 4, 2
• May be associated with underlying conditions such as lymphoma 2

Other Mechanisms

• Intrinsic vascular endothelial dysfunction can cause angioedema independent of mast cell or bradykinin pathways 1, 2
• Idiopathic angioedema (pathogenesis unknown) may be histaminergic (mast cell-mediated) or nonhistaminergic with undefined mediator pathways 4

Critical Diagnostic Distinctions

The presence or absence of urticaria is the key distinguishing feature 1:

• Angioedema with urticaria suggests mast cell-mediated mechanisms (allergic reactions, chronic urticaria) 2
• Angioedema without urticaria warrants evaluation for C1 inhibitor deficiency or ACE inhibitor use 2

Screening approach for recurrent angioedema without urticaria:

• Measure C4 level as initial screening (reduced in 95% of C1 inhibitor deficiency cases) 1, 5
• If C4 is low, measure C1-INH antigenic level and functional activity 5
• Measure C1q level to distinguish hereditary from acquired C1 inhibitor deficiency 5
• Always inquire about ACE inhibitor or ARB use 2

Common Pitfalls

• ACE inhibitor angioedema can persist for at least 6 weeks after drug discontinuation, and the propensity for swelling continues during this period 1, 6
• Standard allergy treatments (antihistamines, corticosteroids, epinephrine) are not reliably effective for bradykinin-mediated angioedema 6, 5
• Hereditary angioedema does not present with urticaria—if urticaria is present, consider alternative diagnoses 2
• Switching from ACE inhibitor to ARB carries a 2-17% recurrence risk, though most patients (>80%) tolerate ARBs without recurrence 5