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Diagnosis and Management of Hereditary Angioedema

Diagnosis and Management of Hereditary Angioedema

Hereditary angioedema (HAE) is an autosomal-dominant disorder caused by deficiency of C1 esterase inhibitor (C1-INH). It is estimated that HAE affects 1 out of every 30,000 people worldwide. The most common type of HAE—type I—is seen in 85% of patients. These patients have low C1-INH levels, whereas patients with type II HAE (approximately 15%) have normal levels of C1-INH but decreased function. Type III HAE is extremely rare and seen in patients with normal C1-INH levels and function.

HAE is characterized by recurrent episodes of cutaneous swelling, typically involving the face, extremities, or genitalia. The episodes are nonpruritic and not associated with urticaria. The most common symptoms include facial swelling, tongue swelling, throat swelling, and abdominal pain. Swelling from HAE can also involve the GI tract and cause severe abdominal pain, often mimicking clinical presentation of an acute abdomen and leading to unnecessary surgical procedures. The airway can also be subject to dangerous swelling, and laryngeal edema can be life-threatening and lead to asphyxiation. It is not unusual for HAE attacks to be triggered by dental or surgical procedures, illness, or stress. Unlike idiopathic angioedema, HAE will not respond to antihistamines or systemic corticosteroids.

HAE usually presents in late childhood and persists throughout life; the frequency of episodes can vary and be unpredictable. This unpredictability can cause emotional distress and lead to reduced quality of life, disrupted work/school, or limitation in social activities for patients. Patients with HAE most frequently report having monthly episodes which can lead to recurrent hospital visits.

Diagnosis of HAE starts with a thorough history and physical exam. Assessing for family history of HAE is important due to the inherited nature of the condition, but HAE can also develop spontaneously. The most useful screening test is measuring serum C4 levels, which will be low in HAE. Evaluating serum levels of both C1 inhibitor protein level and function are necessary for distinguishing type I from type II HAE. Laboratory testing for factor XII mutations can also be helpful, as are C1q studies, which can evaluate for acquired angioedema.

Management of HAE focuses on reducing morbidity, preventing fatal episodes of angioedema, and improving patient quality of life. On-demand therapies are available for patients for prompt treatment of HAE attacks when they occur. These therapies include IV plasma-derived C1-INH, subcutaneous ecallantide, subcutaneous icatibant, and IV recombinant human C1-INH. When these acute agents are not available, fresh frozen plasma (FFP) is recommended as treatment for acute HAE attacks.

There are also short-term prophylactic treatments that can be taken before surgical or dental procedures. For patients who experience frequent episodes, long-term prophylactic therapies are available. The decision to start long-term prophylaxis depends on attack severity and frequency, as well as history of laryngeal attacks. Long-term prophylactic agents include danazol, nano-filtered plasma-derived human C1-INH, subcutaneous plasma-derived C1-INH, and a subcutaneous kallikrein inhibitor known as lanadelumab. There are numerous treatments that can be given in the home setting by patient self-injection or home healthcare, which has provided more options for patients.

It is important to mention that diagnosis of HAE can often be delayed, with a delay of 1 to 6 years for most patients. Clinicians who work in the family practice, pediatric, emergency medicine, and urgent care settings need to be aware of the presentation of HAE and promptly refer patients to allergy/immunology for proper evaluation. Workup for HAE—including C1 inhibitor function, C1 inhibitor protein, C4 levels, and C1q levels—can help the specialist distinguish which type of angioedema is affecting your patient.

  • Bernstein JA. HAE update: epidemiology and burden of disease. Allergy Asthma Proc. 2013;34:3.
  • Bork K, et al. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med. 2006;119:267.
  • Riedl M, et al. Current medical management of hereditary angioedema: Follow-up survey of US physicians. Ann Allergy Asthma Immunol. 2021;126:264.

Filed under: Allergy/Immunology

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