Overview
Definition
Hereditary angioedema (HAE) is a hereditary condition featuring recurrent episodes of swelling (angioedema), usually of the mucosa of the respiratory and gastrointestinal (GI) systems, without urticaria or itching.
Epidemiology
- Worldwide incidence:
- 1 in 50,000–150,000 people
- Represents 2% of clinical angioedema
- No difference in prevalence between genders
- No difference in prevalence between ethnic groups
- 75% of patients present by 15 years of age
- Emergency department (ED) visits due to HAE: 15,000–30,000/year
Etiology
Genetic mutations are the cause of HAE:
- Inherited mutations in the gene for the C1 esterase inhibitor (C1-INH): mapped to 11q12-13.1
- Autosomal dominant disease
- Transmission: 50% probability of transmission to children of either gender
Pathophysiology and Types
The basic pathophysiology of swelling in HAE has to do with the overproduction of bradykinin.
| HAE type I | HAE type II | HAE type III | |
|---|---|---|---|
| Prevalence | 80%–85% of cases | 15%–20% | Very rare; usually in women |
| Cause | Reduced secretion of C1-INHs | Production of non-functional C1-INH |
|
| Pathophysiology | Excess production of inflammatory anaphylatoxins that affect the flow of body fluids between the vascular system and body tissues | Excess production of inflammatory anaphylatoxins that affect the flow of body fluids between the vascular system and body tissues |
|
Clinical Presentation
Patients with HAE have recurrent attacks:
Angioedema attack
- Cutaneous symptoms:
- Swelling of skin in non-dependent areas
- Seen most commonly on face and genitals
- Swelling increases over 24 hours and subsists over the following 48 hours.
- GI symptoms:
- Symptoms of colic, nausea, vomiting, and diarrhea
- Often preceded by prodromal symptoms of fatigue, hunger, irritability, and rash
- Airway symptoms:
- Swelling of the lips, tongue, uvula, or palate
- Early symptoms may include voice changes, sore throat, and “barky” cough
- Severe episodes may cause airway obstruction and suffocation.
- More than ½ of patients will experience airway symptoms.
Severe face, tongue, and pharyngeal edema in a patient treated with an angiotensin- converting-enzyme (ACE) inhibitor
Image: “F3” by the National Allergy, Asthma, and Urticaria Centers of Charleston, Charleston, SC. License: CC BY 2.0.
Angioedema of the face
Image: “Angioedema of the face” by S. Tolga Yavuz et al. License: CC BY 4.0.
Hereditary angioedema
Image: “Typical features” by the Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland. License: CC BY 4.0.
Triggers
- Illness:
- Upper respiratory infection
- H. pylori infection
- Trauma:
- Intubation
- Dental work
- Piercings
- Medication:
- ACE inhibitors
- Tamoxifen
- Some hormone replacement medications
Diagnosis
History and physical exam
Recognizing HAE is often difficult due to a wide variability in disease expression:
- May be similar to other types of angioedema resulting from allergies or other medical conditions
- HAE should be considered if the patient presents with:
- Recurrent angioedema (without urticaria)
- Recurrent episodes of abdominal pain and vomiting
- Laryngeal edema
- Positive family history of angioedema
Laboratory testing
Blood tests often used to confirm the diagnosis:
- Serum complement factor 4 (C4): most reliable and cost-effective screening test
- C1-INH antigenic protein
- C1-INH functional level (if available)
| Type of angioedema without urticaria | C1-INH protein | C1q | C4 & C2 |
|---|---|---|---|
| HAE type I | ↓ | Normal | ↓ |
| HAE type II | N or ↑ (but dysfunctional) | Normal | ↓ |
| Acquired angioedema with C1-INH deficiency (type I) | ↓ | ↓ | ↓ |
| Acquired angioedema with C1-INH deficiency (type II) | ↓ | ↓ | ↓ |
Management
There is no chronic preventive treatment; management focuses on treating attacks based on specific symptoms:
- Medications used in all acute attacks as soon as symptoms start:
- C1-INHs: 1st-line treatment:
- Concentrates from human plasma
- Recombinant forms
- Bradykinin B2-receptor antagonist
- Kallikrein inhibitors (available in the United States only)
- C1-INHs: 1st-line treatment:
- Airway symptoms:
- Airway management
- Intubation should be considered early.
- GI symptoms:
- Supportive care and close monitoring
- Rehydration may be necessary.
- Monitor for signs of intestinal occlusion from swelling.
- Cutaneous symptoms: usually with medication only
- Preventative therapy: C1-INH is often administered 1–1.5 hours before surgery.
References
- Nordenfelt, P., Nilsson, M., Björkander, J., Mallbris, L., Lindfors, A., & Wahlgren, C.F. (2016). Hereditary Angioedema in Swedish Adults: Report From the National Cohort. Acta Derm Venereol. May;96(4):540-5. doi: 10.2340/00015555-2274. PMID: 26540175.
- Bork, K., Meng, G., Staubach, P., & Hardt, J. (2006). Hereditary angioedema: New findings concerning symptoms, affected organs, and course. Am J Med. Mar;119(3):267-74. doi: 10.1016/j.amjmed.2005.09.064. PMID: 16490473.
- Bork, K., Frank, J., Grundt, B., Schlattmann, P., Nussberger, J., & Kreuz, W. (2007). Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant). J Allergy Clin Immunol. Jun;119(6):1497-503. doi: 10.1016/j.jaci.2007.02.012. Epub 2007 Apr 5. PMID: 17418383.
