Hereditary Angioedema Clinical Presentation

Updated: Aug 30, 2018
  • Author: Michael M Frank, MD; Chief Editor: Michael A Kaliner, MD  more...
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Patients with hereditary angioedema (HAE) typically report episodic attacks that begin during childhood and become more severe during adolescence. [13, 19] Attacks in childhood usually are mild and infrequent and commonly manifest as abdominal involvement. A family history of HAE is typically obtained, although spontaneous mutations may occur.

Attacks are often preceded by a prodrome associated with a tingling in the area that will swell 1-2 hours before the swelling starts. Sudden mood changes, anxiety, sensory changes, or exhaustion may also occur several hours in advance of attacks.

Trauma precipitates attacks in about one third of patients. The trauma usually is pressure rather than sharp trauma. Patients who stand in one spot for a long time may have foot swelling; patients who used a lawn mower may have hand swelling. In some cases, infections may trigger attacks, and some women note attacks at the time of menses. However, most attacks have no clear inciting event.

The frequency of attacks varies greatly among affected individuals and at different times in the same individual, with some experiencing weekly episodes, while others might go longer than a year between attacks.

Symptoms are referable to 3 prominent sites: subcutaneous tissues (face, hands, arms, legs, genitals, and buttocks); abdominal organs (stomach, intestines, bladder, and kidneys), which may manifest as vomiting, diarrhea, or paroxysmal colicky pain and mimic a surgical emergency; and the upper airway (larynx) and tongue, which may result in laryngeal edema and upper airway obstruction. Attacks usually occur at a single site, but simultaneous involvement of subcutaneous tissue, viscera, and the larynx is not uncommon.

Patients often report that episodes of swelling worsen over a period of 12-24 hours, usually with resolution within 72 hours. Symptoms can persist for up to 5 days, with migration of swelling to different sites. The edema is usually unresponsive to antihistamines. Attacks are usually periodic and are commonly followed by weeks of remission.

Nonpitting cutaneous swelling is the most commonly reported symptom, and it mainly affects the extremities, the genitalia, and the face. [13, 19] Patients first notice a tightness or tingling of the skin, followed by the development of angioedema that evolves over several hours. In some patients, attacks are preceded by the development of a rash that is erythematous, not raised, and not pruritic, known as erythema marginatum. The angioedema typically resolves over 1-3 days.

Acute abdominal pain, nausea, and vomiting are the dominant symptoms in 25% of patients with HAE and are rarely seen in people with other forms of angioedema. The abdominal pain is caused by edema of the mucosa of any portion of the gastrointestinal tract. The intensity can approximate that of an acute abdomen, often resulting in unnecessary surgery. Either constipation or diarrhea can be noted. The gastrointestinal edema generally follows the same time course to resolution as the cutaneous attacks.

Laryngeal edema is the most feared complication of HAE and can cause an immediate life-threatening emergency. The lifetime incidence of a laryngeal attack is estimated at 70%. The injection of a local anesthetic into the gums for the purpose of dental work is a common precipitant, but laryngeal edema can be spontaneous.

Laryngeal edema may progress rapidly through mild discomfort to complete airway obstruction, usually over a period of hours. Often, the pharyngeal swelling is difficult to visualize, in which case progression of the disease can best be evaluated by asking the patient if the attack is progressing. Difficulty with secretions and a change in the tone of the voice are good measures of progression. Emergency intubation or tracheostomy may be necessary to ensure an adequate airway.

Less common presentations reflect edema at other sites. Scrotal or even penile swelling is fairly common in males. Similarly, some women note swelling of the labia in attacks. Mucosal edema of the bladder or urethra can result in urinary retention, stammering, pain, or anuria.

Episodes of severe headaches, visual disturbances (eg, blurred vision, diplopia), and ataxia have been reported. Cases of painful muscle swelling and unilateral hip or shoulder involvement have also been cited.

Patients with HAE have a propensity to develop autoimmune disease. [20] This may range from inflammatory bowel disease to systemic lupus erythematosus (SLE) to thyroiditis, and, although these diseases are usually mild, they should be considered.


Physical Examination

Patients having acute attacks of HAE may appear severely ill. The first priority in the evaluation is to ensure an adequate airway. With severe attacks, patients can develop hypotension, owing to sequestration of fluid in the extravascular space.

Physical signs of hereditary angioedema (HAE) include overt, noninflammatory swelling of the skin and mucous membranes. Typical involvement includes the face, hands, arms, legs, genitalia, and buttocks, although the edema can localize subcutaneously at any site. Patients with HAE with normal C1 inhibitor levels tend to have more facial attacks. [13] In some patients with severe edema, tension vesicles or bullae may develop. Patients should not be febrile if HAE is their only active problem.

In approximately 25% of patients, erythema may precede the occurrence of edema. An estimated 30-50% of patients with HAE reportedly have erythema marginatum preceding or accompanying the attacks. Urticaria is not usually associated with HAE. [4]

Abdominal examination may reveal signs consistent with acute abdomen or abdominal obstruction. Ascites is often present with an abdominal attack associated with angioedema.

Mucosal involvement with glossal, pharyngeal, or laryngeal edema may cause respiratory obstruction and signs of distress.

Additional rare physical findings that have been reported are pleuritic symptoms with pleural effusions, seizures and hemiparesis secondary to cerebral edema, and bladder edema.