Hereditary Angioedema: Recognition and Treatment

Lilian White, MD
March 9, 2026

Hereditary angioedema (HAE) is a rare genetic disorder that affects 1 in 50,000 to 1 in 100,000 people in the United States; there are 7 types of disorder. Approximately 90% of HAE is due to C1 inhibitor deficiency (type 1 or type 2 HAE). HAE does not appear to have a higher prevalence in any ethnic group. Type 1 and type 2 HAE are often diagnosed in early childhood and worsen with puberty. Inheritance of HAE is autosomal dominant (approximately 75%). De novo mutations (approximately 25%) are also possible. Medical costs of prophylactic treatment of HAE are significant at an estimated $500,000 per year per patient.

A key presenting symptom of HAE is angioedema without wheals. Edema associated with HAE is often asymmetric, nonpitting, and disfiguring and does not resolve spontaneously (often lasting 2-5 days).  Unlike urticaria, pruritus is absent in HAE. Approximately 30% of patients with these symptoms have HAE. Increased vascular permeability leads to swelling of the subcutaneous, mucosal, or submucosal tissue. Patients may experience attacks of swelling in regions of cutaneous tissues or organs (eg, genitalia, bladder, joints), including the abdominal viscera, which may mimic symptoms of appendicitis. Swelling of the larynx can be lethal and may be the initial presenting sign of type 1 or type 2 HAE. It is estimated that more than 50% of patients with type 1 HAE will have a laryngeal attack in their lifetime.

HAE is rare, and delay in diagnosis is common, with an average time to diagnosis of 8 years. Misdiagnosis is also common (approximately 65%), with up to 24% of patients in one study undergoing abdominal surgery as a result of symptoms (eg, appendectomy). The most common misdiagnosis is allergies. Urticaria and pruritus distinguish allergies from angioedema (in which this sign or symptom is not present). Recurrent attacks of cutaneous swelling without urticaria or pruritus raises the suspicion for HAE. Stress is the most common trigger of attacks. 

The diagnosis of HAE is made based on clinical history and supportive laboratory findings. Types 1 and 2 HAE have low serum C4 levels and C1 inhibitor levels. Genetic sequencing may be helpful but is not required for a diagnosis. Different types of HAE may have normal C1 inhibitor levels and genetic mutations. Testing is recommended for first-degree relatives of patients with HAE because of the potential for life-threatening angioedema in relatives.

Treatment of HAE comprises addressing acute attacks and providing short- and long-term prophylaxis. Antihistamines, epinephrine, and glucocorticoids used for the treatment of histamine- or mast cell–mediated edema are not effective. For acute attacks, plasma-derived C1 inhibitor is an option, among others. In the past, fresh, frozen plasma was the preferred treatment, but it has fallen out of favor because of the potential to worsen the attack. 

Short-term prophylaxis may be considered before triggering events, such as medical or dental procedures. Options for short-term prophylaxis include plasma-derived C1 inhibitor within 2 hours or danazol 400 to 500 mg/day a week before the procedure. These treatment options are most effective for types 1 or 2 HAE, but they also may be considered for other types of HAE. Long-term prophylaxis includes plasma-derived C1 inhibitors and kallikrein inhibitors, among others. Epinephrine is not effective for treating patients with an acute attack of HAE, so a medical alert bracelet or alert in a patient’s electronic record may be considered to guide treatment in the case of an emergency. 

Exogenous estrogens or ACE inhibitors may worsen symptoms and are not recommended in patients with HAE. Progestins, tranexamic acid, and attenuated androgens such as danazol may be helpful for the treatment of HAE in patients with a normal C1 inhibitor level.