Symptoms of HAE

Hereditary angioedema (HAE) is characterized by acute, recurrent attacks of localized edema. Edema related to HAE does not respond to epinephrine, antihistamines or glucocorticoids.

Once edema begins, it usually develops rapidly over a 24-hour period, and then subsides over several (usually 1 to 5) days. Approximately 30% of patients have more than 12 HAE attacks a year (Agostoni and Cicardi 1992).

The attacks seem to occur spontaneously and with no apparent cause, but anxiety, stress, trauma, dental and surgical procedures, as well as viral and bacterial infections have been cited as potential triggers. Female patients report an increase in attacks during the menses. Similarly, ACE inhibitors, oral contraceptives and female hormonal treatments are known triggers of HAE attacks (Agostoni and Cicardi 1992).

The age of onset varies, but statistics show that 40% of patients experience HAE symptoms before age 12 (Gompels, et al. 2005). Prodromal symptoms may include erythema marginatum, fatigue (vague), tingling, nausea, rumbling, bowel movement changes, and flu-like feelings.

Although it may be uncomfortable and disfiguring, swelling that results from an attack of HAE is non-pruritic and often painless. HAE attacks can involve subcutaneous tissue, intestines, face, hands, feet, genitalia, and most important, the larynx.

Laryngeal edema: Laryngeal attacks of HAE are the most dangerous, since laryngeal, nasal, and sinus edema can compromise the airway. Approximately 50% of all HAE patients experience at least one laryngeal attack and some patients have them repeatedly (Bork, et al. 2003). Mortality rates are estimated at 15%-33% (Heymann 2006).

Abdominal edema: HAE-related abdominal edema causes acute abdominal pain, which progresses to nausea, vomiting, and often diarrhea as the attack evolves. Some patients report the onset of nausea minutes, hours, or even a day or two before the onset of an attack. During an attack, the abdomen is usually tender to palpation. Thus, this type of attack can be difficult to distinguish from a surgical emergency. Yet, even if untreated, symptoms usually subside within several days. Unfortunately, some patients undergo unnecessary surgical procedures before HAE is diagnosed in them (Nzeako, et al. 2001).

In an advisory board meeting hosted by CSL Behring, physicians identified characteristics that differentiate HAE from other forms of angioedema. These can be summarized using the ABCs of HAE or 8 Simple Questions.

ABCs of HAE

Again and Again
HAE attacks tend to recur. Onset often occurs by the second decade of life and symptoms may have worsened over the years.

Body Part: Migratory, Unilateral
HAE attacks are migratory, tend to be unilateral, and may occur in different anatomical sites—not on the same day or during the same attack, but during different attacks on different days. The most common sites for attacks are:

• Extremities
• Intestines (abdominal pain)
• Face
• Genitals
• Larynx

Conjunctiva: Not Involved
Unlike allergic reactions in which the conjunctiva is irritated, itchy, and watery, HAE attacks are not typically associated with itchy, watery eyes.

Drugs
Unlike allergic angioedema, HAE will not respond dramatically to epinephrine, antihistamines, or corticosteroids. HAE attacks will spontaneously improve over time, and it may mistakenly appear that these drugs are weakly effective. Some physicians believe that epinephrine may be useful if given early enough in an attack.

Edema: Non-pitting, Non-pruritic
Although the location of an HAE attack can vary, the non-pitting edema associated with it is non-pruritic.

Family History
Although de novo mutations can occur, HAE is an autosomal dominant disease. A history of family members with similar attacks or a relative who "choked to death" may lend credence to a diagnosis of HAE.

Gastrointestinal Surgery
Because of acute attacks of abdominal pain, people with HAE have often undergone unnecessary laparoscopic surgeries or even appendectomies. A history of these surgeries increases the suspicion of HAE.

8 Simple Questions
Patients who answer "yes" to all or most of the first 7 questions and "no" to question 8 may require further workup for HAE.

	Have you had unexplained attacks of swelling in your hands, feet, arms, legs, face, throat, or genitals?
	Have these swelling attacks occurred on just one side of your body, for example, just your left hand or just your right foot?
	Have you had unexplained attacks of abdominal pain?
	Have these attacks of swelling or abdominal pain occurred more than once?
	Has anyone in your family had similar episodes of swelling or abdominal pain? Or has anyone in your family “choked to death?”
	Do you sometimes feel warning signs (such as fatigue, tingling, nausea, or flu-like symptoms) that an attack will begin—minutes, hours, or even days before an attack?
	Have medications, such as Benadryl®, EpiPens®, or steroid shots, provided little, if any, relief?
	When you’ve had these attacks have your eyes been watery or itchy?

Suspicion of HAE

For more information about HAE see: