What is the workup and management of angioedema (also known as angioneurotic edema)?

Workup of Angioneurotic Edema

The workup of angioedema begins with immediate airway assessment, followed by measurement of C4, C1-INH antigen, and C1-INH functional activity to differentiate hereditary angioedema (HAE) from acquired C1-INH deficiency and other forms, while obtaining detailed medication and family history to identify drug-induced or familial causes. 1, 2

Immediate Clinical Assessment

First, assess for airway compromise immediately as this determines whether the patient requires emergent intervention versus systematic diagnostic workup. 3, 2 Look specifically for:

• Change in voice, loss of ability to swallow, or difficulty breathing 3
• Oropharyngeal or laryngeal involvement requiring monitoring in a facility capable of intubation or tracheostomy 3
• Non-pitting edema affecting skin, mucous membranes, face, or upper aerodigestive tract 2

Document the episode with photographic evidence, laryngoscopic findings, or imaging to confirm true angioedema and exclude mimics like lymphedema, myxedema, or factitious cases. 2 For abdominal presentations, obtain CT or ultrasound showing bowel wall edema and intraperitoneal fluid. 2, 4

Essential History Components

Obtain detailed information on:

• Medication history: Specifically ACE inhibitors (associated with angioedema in 0.1-0.7% of patients), ARBs, NSAIDs, and DPP-4 inhibitors 5, 2
• Family history: Recurrent similar episodes suggesting hereditary forms 2
• Presence or absence of urticaria: Angioedema without hives suggests bradykinin-mediated rather than mast cell-mediated disease 5, 2
• Triggers: Estrogen therapy, stress, trauma, or procedures 5
• Age of onset: Childhood/young adulthood suggests hereditary forms; later onset may indicate acquired C1-INH deficiency 5

Laboratory Diagnostic Algorithm

First-Line Testing

Measure C4 level, C1-INH antigen, and C1-INH functional activity to exclude C1-INH deficiency as the initial diagnostic step. 1, 2

Interpretation:

• Low C4 with low C1-INH (antigen or function): Confirms C1-INH deficiency 2
• Normal C1-INH levels: Proceed to evaluate for HAE with normal C1-INH or other causes 5

Second-Line Testing (When C1-INH Deficiency Confirmed)

If acquired C1-INH deficiency is suspected based on age of symptom onset (typically >40 years), measure: 1, 2

• C1q level: Normal C1q suggests hereditary form; low C1q indicates acquired deficiency 2
• Anti-C1-INH antibodies: May be present in acquired forms 5, 1
• Screen for underlying conditions: Lymphoma or other malignancies, as acquired C1-INH deficiency may be associated with C1INH autoantibodies with or without underlying conditions 5

Additional Testing for HAE with Normal C1-INH

For patients with suspected HAE with normal C1 inhibitor, targeted genetic screening may identify pathogenic variants in genes such as Factor XII, plasminogen, angiopoietin-1, kininogen, or myoferlin. 5, 1 However, there are no commonly agreed upon diagnostic criteria for HAE with normal C1-INH levels at this time. 5

Differentiating Angioedema Types

ACE Inhibitor-Induced Angioedema

• Mechanism: Impaired degradation of bradykinin 5
• Management: Immediate and permanent discontinuation of ACE inhibitor 5
• Risk factors: African American patients, smokers, older individuals, and females are at higher risk 3
• ARB consideration: Modest risk of recurrent angioedema exists when switching to ARBs, though most patients can safely use ARBs without recurrence 5

Hereditary Angioedema (HAE-C1INH)

• Diagnosis: Reduced C1INH function with low C4 5
• Inheritance: Autosomal dominant 6
• Clinical features: Recurrent attacks of skin, gastrointestinal, or laryngeal edema without urticaria 6

Acquired C1-INH Deficiency

• Diagnosis: Reduced C1INH function, activation of complement, reduced C1 antigenic levels, and low C1q 5
• Mechanism: Enhanced catabolism of C1INH 5
• Associated conditions: May be associated with lymphoma or C1INH autoantibodies 5

HAE with Normal C1-INH

• Diagnosis: Recurrent angioedema without hives, normal C1-INH levels and function 5
• Triggers: Some kindreds require high estrogen levels for manifestation 5
• Mechanism: Caused by increased bradykinin signaling 5

Critical Pitfalls to Avoid

• Do not delay airway assessment: Laryngeal attacks have historical mortality rates of approximately 30% or higher 1
• Do not assume all angioedema is allergic: Standard treatments (epinephrine, corticosteroids, antihistamines) are NOT effective for HAE or ACE inhibitor-induced angioedema 1, 3
• Do not miss medication-induced causes: ACE inhibitors are a common and reversible cause 5, 7
• Do not overlook abdominal presentations: HAE can mimic surgical abdomen with severe abdominal pain, and patients may develop profound hypovolemic shock from fluid sequestration 4
• Do not perform unnecessary laparotomy: Imaging showing bowel wall edema and peritoneal fluid confirms angioedema and avoids surgical intervention 2, 4

Special Populations

Pregnancy

• Increased attack frequency and severity may occur during pregnancy 5
• Androgens are contraindicated for long-term prophylaxis; plasma-derived C1-INH is preferred 5

Female Patients with HAE-FXII

• Estrogen-triggered symptoms are common 2
• Average age of onset: 20 years 2
• Avoidance of estrogen therapy is important to decrease attack frequency 5