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HAE Management and Treatment

CE / CME

Expert Guidance on HAE Management and the Evolving Landscape of Prophylaxis

Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit

Nurse Practitioners/Nurses: 0.50 Nursing contact hour

Physicians: maximum of 0.50 AMA PRA Category 1 Credit™

Released: March 25, 2025

Expiration: March 24, 2026

Marc Riedl
Marc Riedl, MD, MS
CME/CE Information

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Clinical Features of Hereditary Angioedema

A major challenge in diagnosing HAE is to differentiate its diagnostic criteria from other angioedemas and systemic diseases.3 Starting with the clinical features of HAE, healthcare professionals (HCPs) should first recognize that this is a rare genetic condition. It is much less common than angioedema that is caused by allergic or mast cell mechanisms. The global prevalence of HAE is estimated to be about 1 in every 50,000 people.4

HAE has some clinical features that are important for HCPs to keep in mind when assessing patients in the clinical setting. Of importance, HAE is an angioedema without urticaria (or hives). It causes submucosal or subcutaneous swelling episodes that affect the face and extremities, really anywhere on the skin, as well as the gastrointestinal and genitourinary tracts. HAE can also affect the airway, which is a very concerning feature because it can lead to fatalities from asphyxiation.

There is often a family history of HAE. Approximately 75% of patients will have a parent with the same symptoms of HAE. Further, there is a 50% chance that a parent with HAE will pass this disorder on to their child. As it is an autosomal dominant disorder, HAE affects men and women equally.5,6

There are 3 types of HAE, with type 1 or 2 being the most common. HAE type 1 (HAE-1) occurs when insufficient functional C1-INH protein is produced in the body; HAE type 2 (HAE-2) occurs when C1-INH protein is produced at sufficient levels but is dysfunctional—it does not have the appropriate inhibitory properties, so the functional levels are very low. Both HAE-1 and HAE-2 are caused by mutations to the SERPING1 gene. The third type is called HAE with normal C1-INH (HAE-nC1-INH). Although these patients have no C1-INH deficiency, they present with similar symptoms of HAE-1/2 and may have mutations in other genes such as F12, PLG, or KNG1 (not SEPRING1). This is currently an active area of research because HAE-nC1-INH is a condition that we do not fully understand. There are also emerging genetic tests to better identify patients with HAE and their specific type.7

Symptoms of HAE include angioedema attacks without hives. They are often protracted and last up to 5 days, with a progressive course that increases over the first 24 hours before peaking and slowly resolving. These angioedema attacks are unresponsive to allergy medications, such as antihistamines, corticosteroids, or epinephrine, which is an important clue in the clinical setting. Symptoms that do not get better with the usual cocktail of allergy treatment given in the hospital or emergency department is a red flag; HCPs should consider HAE in these cases.8 Further, HAE attacks are unpredictable and variable. Some patients will have 1 attack per week; others will have 1 or 2 attacks per year. In addition, the course of an attack is unpredictable, even among patients over their lifetime, which is one of the frustrating and frightening things about this disorder.

There are triggers that will make patients’ symptoms worse, including certain medications like estrogen-containing contraceptives and angiotensin-converting enzyme inhibitors. Trauma or stress can also trigger HAE attacks, including dental surgery and other surgical traumas, a major life event (either good or bad), or trouble at work.1

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Diagnosing HAE

This table references the evidence-based guidelines and reminds us of the important clinical features of HAE, whether you look at the US or international guidelines. HCPs should consider HAE in anyone who has recurrent angioedema episodes, particularly in the absence of hives, as well as a family history of similar symptoms.

Patients are often misdiagnosed because HAE is rare and HCPs misidentify their symptoms as a result of an allergy, abdominal, gynecologic, or gastrointestinal issue/disorder. Because of this, patients may undergo ineffective treatments or surgery, leading to increased burden, morbidity, and mortality risk.3

At the bottom of this table are the recommended laboratory tests, including serum C4. It is approximately 80% to 95% sensitive, meaning its levels will be low in patients at any given time if there is C1-INH deficiency. Of note, the confirmatory tests are the C1-INH level and function, which will identify HAE-1 vs HAE-2. These labs are critical to either confirm or exclude a diagnosis of HAE-1/2.1,2

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A 28-year-old woman presents to your clinic with a history of recurrent, nonpitting swelling involving her face, extremities, and abdomen. Each episode lasts 2 to 3 days, is not associated with urticaria, and does not respond to antihistamines. Which of the patient's symptoms are most suggestive of HAE?

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