What is hereditary angioedema?

Hereditary Angioedema (HAE)

Hereditary angioedema is a rare genetic disorder characterized by recurrent episodes of potentially life-threatening swelling affecting the skin, gastrointestinal tract, and airway, caused by various genetic mutations that lead to dysregulation of the bradykinin pathway. 1

Types and Pathophysiology

HAE is classified into two main categories:

HAE with C1 Inhibitor Deficiency

• HAE-C1INH: The most common form, caused by mutations in the SERPING1 gene
  • Type I: Characterized by reduced levels of C1 inhibitor protein (85% of cases)
  • Type II: Normal levels but dysfunctional C1 inhibitor protein
• Prevalence: Approximately 1 in 50,000-100,000 people 1

HAE with Normal C1 Inhibitor (HAE-nC1INH)

• Normal C1 inhibitor levels and function but similar clinical presentation
• Genetic variants identified:
  • HAE-FXII: Factor XII mutations (most common HAE-nC1INH)
  • HAE-PLG: Plasminogen mutations
  • HAE-ANGPT1: Angiopoietin-1 mutations
  • HAE-KNG1: Kininogen-1 mutations
  • HAE-MYOF: Myoferlin mutations
  • HAE-HS3ST6: Heparan sulfate-glucosamine 3-O-sulfotransferase-6 mutations
  • HAE-CPN: Carboxypeptidase N mutations
  • HAE-DAB2IP: DAB2IP mutations
  • HAE-UNK: Unknown genetic cause 1, 2, 3

Clinical Presentation

Characteristic Symptoms

• Non-pruritic, non-pitting subcutaneous or submucosal edema 4, 5
• Attacks typically affect:
  • Extremities (50% of attacks)
  • Abdomen (50% of attacks) - can mimic acute abdomen
  • Face and oropharynx
  • Larynx (less common but potentially fatal)
  • Genitourinary tract 4, 5

Attack Progression

• Prodromal symptoms may include erythema marginatum (non-urticarial rash), localized tingling, and skin tightness 4
• Swelling typically worsens over 24 hours
• Gradual resolution over 48-72 hours 4, 5
• Attacks may start in one location and spread to another 5

Key Clinical Features

• Absence of urticaria (with possible exceptions of HAE-CPN and HAE-DAB2IP) 1
• Symptoms often begin in childhood, worsen at puberty
• Unpredictable frequency and severity of attacks 5
• Specific variants may have characteristic presentations:
  • HAE-PLG: Frequent tongue swellings 4
  • HAE-FXII: Particularly sensitive to estrogen 4
  • HAE-MYOF: Primarily facial and oral mucosa involvement 1

Triggers

Common triggers include:

• Physical trauma
• Stress
• Infections
• Estrogen exposure (particularly in HAE-FXII)
• ACE inhibitors (contraindicated in HAE) 4
• Menstruation and warm weather (reported in HAE-MYOF) 1

Diagnosis

Laboratory Testing

• C4 levels (typically low in HAE-C1INH)
• C1 inhibitor levels and function
• Genetic testing for specific mutations 3

Diagnostic Challenges

• Family history is supportive but not required for diagnosis due to:
  • Possibility of de novo mutations
  • Variable penetrance
  • Recall bias
  • Unknown family history due to adoption or estrangement 1
• Symptoms may show significant variability even within families with the same mutation 1

Treatment

Acute Attack Management

First-line treatments include:

• Plasma-derived C1 inhibitor concentrates: Most effective when administered early; preferred in pregnancy 4
• Icatibant (bradykinin B2 receptor antagonist): 30 mg subcutaneously; self-administration possible 4, 6
• Ecallantide (plasma kallikrein inhibitor): Effective but requires monitoring due to anaphylaxis risk 4

In resource-limited settings:

• Fresh frozen plasma (FFP): Contains approximately 1 unit/ml of C1-INH; dosage 10-15 ml/kg or 2 units 4, 1

Prophylaxis

Options include:

• Plasma-derived C1INH replacement: Safe and effective 4
• Lanadelumab: Effective option for long-term prophylaxis 4
• Attenuated androgens (e.g., danazol): Effective but with more side effects; works by increasing C1 esterase inhibitor levels 4, 7
• Antifibrinolytic agents: Less effective than androgens but relatively safe; may be particularly effective for HAE-FXII 4

Special Considerations

Airway Management

• Close monitoring for signs of impending airway closure is crucial
• Early intubation or tracheotomy may be necessary for upper airway angioedema 4

Pregnancy

• Attacks may increase during pregnancy but typically decrease during delivery
• Risk increases during the postpartum period
• Androgens are contraindicated; plasma-derived C1INH is preferred 4

Common Pitfalls

• Misdiagnosis as allergic reactions, leading to inappropriate treatment with antihistamines, corticosteroids, and epinephrine, which are ineffective for HAE 4
• Delayed treatment of acute attacks, especially laryngeal attacks which can be life-threatening 4
• Inappropriate medication use, such as ACE inhibitors or estrogen-containing medications 4
• Inadequate patient education on trigger avoidance and early recognition of attacks 4

Global Disparities in HAE Management

Significant inequities exist in HAE care worldwide:

• Limited access to life-saving acute drugs in low-income countries
• Lack of specialized HAE services or diagnostic facilities in many regions
• Long delays in diagnosis in resource-limited settings 1

Early recognition, prompt treatment of acute attacks, and appropriate prophylaxis are essential to reduce morbidity and mortality in patients with HAE.