What are the diagnostic criteria and treatment options for hereditary angioedema?

Hereditary Angioedema Diagnosis

Hereditary angioedema (HAE) should be suspected in all patients presenting with recurrent angioedema without hives that fails to respond to antihistamines, corticosteroids, or epinephrine, and diagnosis requires measurement of C4, C1-INH antigen level, and C1-INH functional activity. 1, 2

Diagnostic Criteria

Clinical Presentation Features

The diagnosis begins with recognizing key clinical characteristics that distinguish HAE from other forms of angioedema:

• Recurrent episodes of non-pitting, localized swelling affecting subcutaneous or submucosal tissues without accompanying urticaria (hives) 3
• Slow onset with gradual progression over hours, lasting 2-5 days on average before spontaneous resolution 3
• Common locations include face, upper airways, tongue, gastrointestinal tract, extremities, and genitals 3
• Lack of response to antihistamines, corticosteroids, or epinephrine—a critical distinguishing feature 1, 2
• Typical age of onset between 10-20 years for HAE-C1INH, though symptoms may appear from infancy to adulthood 3, 4

Laboratory Testing Algorithm

Step 1: Initial Complement Testing

Measure three tests simultaneously 1, 2:

• C4 level (screening test—low in HAE-C1INH)
• C1-INH antigen level (quantitative)
• C1-INH functional activity (qualitative)

Interpretation:

• HAE Type 1 (most common, ~75% of cases): Low C4 + Low C1-INH antigen + Low C1-INH function 2, 4
• HAE Type 2: Low C4 + Normal or elevated C1-INH antigen + Low C1-INH function 2, 4
• Normal C1-INH: Proceed to HAE with normal C1-INH (HAE-nC1INH) evaluation 3

Step 2: Exclude Acquired C1-INH Deficiency

If C1-INH is abnormal and patient is >40 years old 3:

• Measure C1q level (low in acquired, normal in hereditary) 2, 5
• Test for anti-C1-INH antibodies 3, 1

Step 3: Exclude Medication-Induced Angioedema

Discontinue suspected medications and observe for 1-2 months 3:

• ACE inhibitors (most common drug cause, 30-40% of ED angioedema cases) 2
• ARBs, NSAIDs, DPP-4 inhibitors, neprilysin inhibitors 2, 5

Step 4: Exclude Mast Cell-Mediated Angioedema

Trial of high-dose antihistamines (4× standard dose) plus montelukast for adequate duration 3:

• If responsive, diagnosis is mast cell-mediated angioedema 3
• If unresponsive, consider 4-6 month trial of omalizumab 3
• Response to these medications excludes HAE 3

Step 5: Genetic Testing for HAE-nC1INH

When C1-INH levels are normal but clinical suspicion remains high, perform targeted gene sequencing 3, 1:

Known pathogenic variants 3:

• F12 (Factor XII): Most common, accounts for 83.4% of HAE-nC1INH families, particularly c.983C>A (p.Thr328Lys) mutation 3
• PLG (Plasminogen): c.988A>G (p.Lys330Glu) 3
• ANGPT1 (Angiopoietin-1): c.807G>T (p.Ala119Ser) 3
• KNG1 (Kininogen-1): c.1136T>A (p.Met379Lys) 3
• MYOF (Myoferlin): c.651G>T (p.Arg217Ser) 3
• HS3ST6: c.430A>T (p.Thr144Ser) 3

Step 6: Therapeutic Trial

In absence of identified pathogenic variant, trial of bradykinin B2 receptor antagonist (icatibant) during an acute attack 3:

• Prompt and durable response supports bradykinin-mediated angioedema diagnosis 3
• Lack of response does not exclude HAE 3
• Consider trial of tranexamic acid for long-term prophylaxis 3

Step 7: Classification

• HAE-nC1INH with known variant: Confirmed diagnosis when pathogenic variant identified 3
• HAE-UNK (unknown): Positive family history but no identified variant 3
• INMA (idiopathic non-mast cell-mediated angioedema): No family history, no identified variant 3

Family Screening

All first-degree relatives of diagnosed HAE patients should undergo screening 3:

• Clinical history assessment for angioedema episodes 3
• Targeted genetic testing when pathogenic variant identified, regardless of symptom status 3
• Female relatives should be asked about swelling during high-estrogen states (pregnancy, oral contraceptives) 3

Critical Diagnostic Pitfalls

Common Errors to Avoid

• Testing only C1-INH antigen without functional activity: Misses HAE Type 2, where antigen may be normal but function is impaired 1
• Misdiagnosing as allergic angioedema: Leads to inappropriate treatment with antihistamines and steroids, which are completely ineffective in HAE 2, 5
• Failing to document attacks: Photographic evidence, laryngoscopy findings, or imaging during attacks helps differentiate true angioedema from mimics 5
• Not obtaining abdominal imaging during GI attacks: CT or ultrasound showing bowel wall edema confirms diagnosis and prevents unnecessary surgical exploration 5
• Overlooking medication history: ACE inhibitors can cause angioedema years after initiation 2

Special Considerations

• HAE-FXII shows marked female predominance (10-13:1) and estrogen-triggered symptoms 3
• Laryngeal involvement represents life-threatening emergency requiring immediate intervention—particularly common with PLG mutations 2
• Abdominal attacks may mimic acute surgical abdomen; imaging showing bowel wall edema is diagnostic 5
• De novo mutations occur in ~25% of HAE-C1INH cases, so absence of family history does not exclude diagnosis 6

Treatment Overview

Acute Attack Management

First-line treatments for acute HAE attacks 5, 7:

• Plasma-derived C1-inhibitor concentrate (IV infusion) 5
• Icatibant (bradykinin B2 receptor antagonist, FDA-approved for adults ≥18 years) 7
• Ecallantide (kallikrein inhibitor) 5

Administer as early as possible in the attack for maximum efficacy 5.

Resource-limited settings: Fresh frozen plasma may be effective when first-line treatments unavailable 5, 8

Prophylaxis

Long-term prophylaxis for frequent attackers 5, 9:

• Plasma-derived C1-inhibitor (first-line) 5
• Tranexamic acid (antifibrinolytic) 8
• Danazol (attenuated androgen): Start 200 mg 2-3 times daily, individualize based on response by decreasing dose by 50% at 1-3 month intervals; increase by up to 200 mg if attack occurs 9

Short-term prophylaxis before procedures 5:

• Plasma-derived C1-inhibitor 5
• Danazol 5

Critical safety note: Danazol has significant side effects, particularly in children and females, requiring careful risk-benefit assessment 8.