Hereditary Angioedema (HAE)

Hereditary angioedema (HAE) is a rare disorder characterized by recurrent episodes of severe swelling throughout various regions of the body. HAE typically is inherited in an autosomal-dominant pattern, although some cases occur spontaneously. HAE affects 1 in every 50,000 individuals.¹ 

The 3 types of HAE can be differentiated by serum levels of the C1-esterase inhibitor protein and by the genetic root cause. Variations in the SERPING1 gene cause types 1 and 2, whereas variations in the F12 gene cause type 3.¹ 

Patients with types 1, 2, and 3 present with similar symptoms and signs.¹ Severe edema of the skin and mucous membranes develops predominantly in 3 locations: subcutaneous tissues, abdominal organs, and airways. Usually, swelling occurs at a specific location, although multiple sites can be involved concurrently.² 

The C1-esterase inhibitor protein regulates inflammatory responses. In HAE, deficiency of this protein results in the excessive release of bradykinin, an inflammatory peptide and potent vasodilator that increases vascular permeability and causes fluid to leak through blood vessel walls into the surrounding tissues. Fluid accumulation results in the excessive swelling seen in individuals with HAE.¹ 

Subcutaneous Tissues

Commonly affected subcutaneous tissues include those of the face (especially the lips and eyelids), hands, arms, legs, buttocks, and genitals, including the scrotum and penis or the labia.^2,3

Abdominal Organs

HAE may affect abdominal organs, including the stomach and gastrointestinal tract, as well as the bladder, kidneys, and urethra. Patients may present with acute symptoms of diarrhea, nausea, vomiting, or paroxysmal colicky pain. Abdominal symptoms predominate in approximately 25% of people with HAE. Swelling in the gastrointestinal mucosa may result in severe pain, causing patients to undergo unnecessary surgery.²

If swelling affects the bladder, kidneys, or urethra, patients may experience urinary retention, pain, anuria, or urinary stammering.²

Airways

Edema of the upper airways, larynx, pharynx, and tongue may lead to life-threatening obstruction and asphyxiation.^2,3 In addition to difficulty breathing, swelling of the throat and larynx causes dysphagia, dysphonia, and stridor.

The estimated incidence of laryngeal edema in patients with HAE is approximately 70%. A common trigger of laryngeal edema is the injection of local anesthetics into the gums before dental work. Laryngeal swelling is more difficult to notice; changes in vocal tone and problems with secretions are the best indicators of progressive laryngeal swelling. If severe laryngeal swelling occurs, emergency intubation or tracheostomy ensures that the airways remain open.²

Episodes of Swelling

Episodes of swelling usually start in childhood, evidenced by abdominal symptoms, and worsen throughout adolescence.^1,2 If HAE is untreated, attacks of swelling lasting 3 to 4 days occur every 1 to 2 weeks.¹

Most patients with HAE cannot report any identifiable triggers, although in approximately one-third of individuals, trauma, usually due to prolonged pressure, triggers an attack of swelling.^1,2 Infection (especially a viral illness), stress, injury, severe pain, surgical or dental procedures, and menstruation may also trigger episodes of swelling.^2,3 The frequency of episodes varies from person to person, and sometimes even in the same person.²

During an attack, edema increases over a period of 12 to 24 hours, then usually subsides within 72 hours, although symptoms can last for up to 5 days.² 

Often, people with HAE become aware of an impending attack when they experience prodromal symptoms, such as a sudden change in mood or sensation, anxiety, extreme fatigue, and tingling or tightness of the skin in the exact location where the swelling will occur, several hours before an attack. Some may also experience erythema marginatum, in which a red rash that is not itchy or raised covers the region where swelling will occur.^1,2 According to a literature review, the prodromal signs and symptoms of an HAE attack vary widely.⁴

Additional Symptoms

People with HAE report visual disturbances such as diplopia or blurry vision, ataxia, and severe headaches. Although subcutaneous swelling is most common, painful muscle swelling and unilateral involvement of a proximal joint have occurred in some cases.²

HAE symptoms do not respond to antihistamines, corticosteroids, or epinephrine, a feature that provides an important clue to the correct diagnosis. Additionally, swelling that continues for longer than a week does not indicate HAE.⁵

References

1. Hereditary angioedema. MedlinePlus. Accessed June 8, 2022.
2. Frank MM. Hereditary angioedema clinical presentation. Medscape. Updated August 30, 2018. Accessed June 8, 2022.
3. Hereditary angioedema. National Organization for Rare Disorders (NORD). Accessed June 8, 2022. 
4. Kemp JG, Craig TJ. Variability of prodromal signs and symptoms associated with hereditary angioedema attacks: a literature review. Allergy Asthma Proc. 2009;30(5):493-499. doi:10.2500/aap.2009.30.3278
5. Busse PJ, Christiansen SC, Riedl MA, et al. US HAEA Medical Advisory Board 2020 guidelines for the management of hereditary angioedema. J Allergy Clin Immunol Pract. 2021;9(1):132-150.e3. doi:10.1016/j.jaip.2020.08.046

Reviewed by Harshi Dhingra, MD, on 6/26/2022.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.