Hereditary Angioedema (HAE)

Hereditary angioedema is a rare genetic disorder characterized by recurrent episodes of severe swelling in various parts of the body. Unlike typical allergic reactions, HAE attacks involve deep swelling without hives or itching, and can be life-threatening when they affect the airway. Affecting approximately 1 in 50,000 people worldwide, HAE requires specialized treatment as it doesn't respond to standard allergy medications. With proper diagnosis and management, people with HAE can lead normal, active lives.

🚨 Airway Emergency

CALL 911 IMMEDIATELY for throat swelling, difficulty breathing, voice changes, difficulty swallowing, or any facial/tongue swelling. Laryngeal attacks can be fatal within hours. Standard epinephrine and antihistamines DO NOT work for HAE. Inform emergency responders about HAE diagnosis.

Medical Disclaimer: This information is for educational purposes only and should not replace professional medical advice. Always consult with a qualified healthcare provider for diagnosis and treatment of any medical condition.

Understanding HAE

HAE is caused by a deficiency or dysfunction of C1 esterase inhibitor (C1-INH), a protein that regulates parts of the immune and blood clotting systems. This leads to excessive production of bradykinin, causing blood vessels to leak fluid into surrounding tissues, resulting in angioedema.

Types of HAE

  • Type I HAE (85%):
    • Low levels of C1-INH protein
    • Reduced functional activity
    • Most common form
  • Type II HAE (15%):
    • Normal or elevated C1-INH levels
    • Dysfunctional protein
    • Reduced functional activity
  • HAE with normal C1-INH (formerly Type III):
    • Normal C1-INH levels and function
    • Often estrogen-sensitive
    • Factor XII mutations in some cases
    • Predominantly affects women

Key Characteristics

  • Autosomal dominant inheritance (50% chance to children)
  • 25% of cases are new mutations
  • No racial or ethnic predilection
  • Equal prevalence in males and females
  • Symptoms typically begin in childhood/adolescence
  • Attacks worsen during puberty

Signs and Symptoms

Attack Characteristics

  • Prodrome (warning signs):
    • Tingling sensation
    • Tightness in affected area
    • Non-itchy rash (erythema marginatum)
    • Fatigue or malaise
    • Mood changes
  • Swelling progression:
    • Develops over 12-36 hours
    • Peaks at 24-72 hours
    • Resolves in 2-5 days untreated
    • Non-pitting edema
    • No hives or itching

Common Attack Locations

Peripheral Attacks (most common):

  • Hands and arms
  • Feet and legs
  • Buttocks
  • Genitals
  • Can be disfiguring and disabling

Facial Attacks:

  • Lips
  • Tongue
  • Eyelids
  • Can progress to airway

Abdominal Attacks:

  • Severe cramping pain
  • Nausea and vomiting
  • Diarrhea
  • Abdominal distension
  • Can mimic acute abdomen
  • Often leads to unnecessary surgery

Laryngeal Attacks (25% lifetime risk):

  • Voice changes
  • Difficulty swallowing
  • Feeling of throat tightness
  • Stridor
  • Can be fatal without treatment

Attack Frequency

  • Highly variable between patients
  • Range: few per year to several per week
  • Average: 1-2 attacks per month
  • Can have attack-free periods

Attack Triggers

Common Triggers

  • Physical trauma:
    • Dental procedures
    • Surgery
    • Injury
    • Medical procedures
  • Emotional stress:
    • Anxiety
    • Anger
    • Excitement
  • Hormonal changes:
    • Menstruation
    • Pregnancy
    • Oral contraceptives
    • Hormone replacement therapy
  • Infections:
    • Upper respiratory infections
    • H. pylori infection
  • Medications:
    • ACE inhibitors (contraindicated)
    • Estrogen-containing medications
  • Other triggers:
    • Prolonged pressure
    • Repetitive activities
    • Temperature extremes

Unpredictable Attacks

Many attacks occur without identifiable triggers, making HAE unpredictable and requiring patients to always be prepared with treatment options.

Diagnosis

Clinical Suspicion

  • Recurrent angioedema without urticaria
  • Family history of similar symptoms
  • Recurrent abdominal pain episodes
  • Failure to respond to antihistamines/steroids
  • Onset in childhood/adolescence

Laboratory Testing

For Types I and II:

  • C4 level:
    • Low during and between attacks
    • Excellent screening test
    • Normal C4 makes HAE unlikely
  • C1-INH antigenic level:
    • Low in Type I
    • Normal/high in Type II
  • C1-INH functional level:
    • Low in both Type I and II
    • <50% of normal
  • C1q level:
    • Normal (distinguishes from acquired angioedema)

For HAE with normal C1-INH:

  • All above tests normal
  • Genetic testing for factor XII mutations
  • Clinical diagnosis based on:
    • Recurrent angioedema
    • Family history
    • Estrogen sensitivity
    • Failure of standard treatments

Genetic Testing

  • SERPING1 gene mutations (Types I and II)
  • F12 gene mutations (some normal C1-INH cases)
  • Useful for family screening
  • Prenatal diagnosis available

Differential Diagnosis

  • Acquired angioedema (C1q low)
  • ACE inhibitor-induced angioedema
  • Allergic angioedema (with urticaria)
  • Idiopathic angioedema

Treatment

Acute Attack Treatment

Early treatment shortens attack duration and severity. All patients should have access to on-demand therapy.

First-Line Therapies:

  • C1 inhibitor concentrates:
    • Plasma-derived: Berinert, Cinryze
    • Recombinant: Ruconest
    • IV administration
    • Works within 30-60 minutes
  • Icatibant (Firazyr):
    • Bradykinin B2 receptor antagonist
    • Subcutaneous injection
    • Self-administered
    • Rapid onset of action
  • Ecallantide (Kalbitor):
    • Kallikrein inhibitor
    • Subcutaneous injection
    • Healthcare setting only (anaphylaxis risk)

Treatment Approach:

  • Treat all laryngeal attacks immediately
  • Consider intubation early for airway attacks
  • Treat severe peripheral/abdominal attacks
  • May observe mild attacks
  • Supportive care (fluids, pain management)

Long-Term Prophylaxis

Indicated for frequent attacks (≥1/week), severe attacks, or significant quality of life impact.

Modern Prophylactic Options:

  • Lanadelumab (Takhzyro):
    • Monoclonal antibody
    • Subcutaneous every 2-4 weeks
    • Highly effective
  • Berotralstat (Orladeyo):
    • Oral kallikrein inhibitor
    • Once daily
    • First oral prophylaxis
  • C1 inhibitor prophylaxis:
    • Cinryze IV twice weekly
    • Haegarda subcutaneous twice weekly

Older Options (less preferred):

  • Danazol (androgenic side effects)
  • Tranexamic acid (less effective)

Short-Term Prophylaxis

For procedures or situations likely to trigger attacks:

  • C1 inhibitor 1-2 hours before procedure
  • Especially important for:
    • Dental work
    • Surgery
    • Endoscopy/intubation
  • Have on-demand treatment available

Comprehensive Management

Action Plan

  • Written emergency action plan
  • When and how to treat attacks
  • Emergency contact information
  • Hospital preference with HAE experience
  • Medication dosing instructions

Self-Administration Training

  • IV infusion techniques (C1-INH)
  • Subcutaneous injection (icatibant, prophylaxis)
  • Proper storage of medications
  • Expiration date monitoring
  • Travel considerations

Medical Alert

  • Wear medical alert jewelry
  • Carry emergency card
  • Mobile app with medical information
  • Educate close contacts

Lifestyle Modifications

  • Stress management techniques
  • Avoid known triggers when possible
  • Maintain treatment supplies
  • Regular follow-up with HAE specialist
  • Join support groups

Special Situations

Pregnancy and HAE

  • Attacks may increase, decrease, or stay same
  • C1 inhibitor safe during pregnancy/breastfeeding
  • Avoid danazol (teratogenic)
  • Vaginal delivery usually possible
  • Have C1-INH available during delivery
  • Regional anesthesia preferred

Children with HAE

  • Symptoms often start by age 10
  • Abdominal attacks common
  • May be misdiagnosed as:
    • Appendicitis
    • Allergies
    • Abuse (from bruising)
  • Age-appropriate treatment available
  • School action plan needed

Surgery and Procedures

  • High risk for triggering attacks
  • Pre-procedure prophylaxis essential
  • Have on-demand treatment ready
  • Monitor for 24-72 hours post-procedure
  • Inform entire medical team

Emergency Department

  • Many providers unfamiliar with HAE
  • Bring own medications if possible
  • Have specialist contact information
  • Emphasize HAE doesn't respond to:
    • Epinephrine
    • Antihistamines
    • Corticosteroids

Living with HAE

Quality of Life Impact

  • Unpredictability causes anxiety
  • Work/school absences
  • Activity limitations
  • Travel concerns
  • Financial burden
  • Relationship stress

Coping Strategies

  • Education about condition
  • Connect with HAE community
  • Psychological support
  • Maintain normal activities when possible
  • Plan ahead for events
  • Build support network

Travel Considerations

  • Carry medications in carry-on
  • Letter from physician
  • Extra medication supply
  • Research hospitals at destination
  • Travel insurance coverage
  • Consider prophylaxis for long flights

Career and Education

  • Inform employer/school appropriately
  • Flexible work arrangements
  • Keep medications at work/school
  • Educate key personnel
  • Know your rights under disability laws

Prognosis

Outlook

  • Normal life expectancy with proper treatment
  • Modern therapies dramatically improve quality of life
  • Most patients can lead active, productive lives
  • Laryngeal attacks remain life-threatening risk
  • Early diagnosis and treatment key to outcomes

Disease Course

  • Lifelong condition
  • Attack frequency varies over time
  • May improve after menopause in women
  • Prophylaxis can reduce attacks by >90%
  • Some achieve near-complete control

Future Directions

  • Gene therapy research ongoing
  • New oral medications in development
  • Improved diagnostic tools
  • Better emergency treatments
  • Increased awareness among providers