TIP: The World Allergy Organization recommends that all children of a parent with HAE be tested.
Factors that may be involved in the triggering and/or maintenance of angioedema
The role of C1-INH
C1-INH is a plasma protein that down-regulates several important inflammatory cascades. Deficiencies in either the quantity or quality of this protein can lead to episodes of edema.3
C1-INH is synthesized predominately in the liver, but also by monocytes and other cells in response to proinflammatory cytokine stimulation. It is a key inhibitor in 4 inflammatory cascades.2,3
In the complement system, C1-INH inactivates C1, thereby stopping the production of proteolytic fragments and inflammation-inducing complexes. C1-INH acts on the fibrinolytic system, inhibiting plasmin and thus inhibiting fibrin degradation. In the kallikrein-kinin system, C1-INH prevents the conversion of prekallikrein to kallikrein—and the subsequent formation of bradykinin. C1-INH also acts on the coagulation cascade, inhibiting Factors XIIa and X1a.2,3
Factors involved in edemagenesis
Which factor or factors are responsible for triggering attacks and the subsequent angioedema remains a subject of controversy. Studies have demonstrated that activation of the kinin system and increased bradykinin concentrations may be responsible for the vasodilation and capillary leakage associated with clinical flares.2,3 However, other components of the alternative pathways that C1-INH regulates may play a role in the initiation and continuation of the expression of bradykinin.3
3 types, characterized by plasma levels and functionality of the C1-INH protein
The variants of HAE related to C1-INH function are:
Acquired angioedema (AAE) is very rare and is due to immune complexes that are usually linked to an underlying lymphoproliferative disorder.5
Occurs equally in
men and women
The most common:
~85% of people
C1-INH does not
Occurs equally in
men and women
~15% of people
More common in
women than men
Not well understood:
C1-INH lab tests are normal but a person still has symptoms of HAE
Descriptions for general, laryngeal, and abdominal attacks
HAE is characterized by acute, localized edema, often involving the subcutaneous tissue, abdomen, face, hands, feet, genitalia, and larynx.2 Although it may be uncomfortable and disfiguring, swelling that results from an attack of HAE is non-pruritic.2 The age of onset varies, but statistics show that 40% of patients experience HAE symptoms before age 5.5
Prodromal symptoms may include6:
Once an HAE attack begins, angioedema usually worsens over a 24-hour period, and then subsides over several days (usually 2–5).5 Approximately 30% of patients have more than 12 HAE attacks a year.7
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 1 laryngeal attack, and some patients have them repeatedly.2 Prior to effective HAE treatments, mortality rates were approximately 30%.8 Current treatments have helped improve the prognosis for those with HAE.
Abdominal edema: HAE-related abdominal edema causes acute abdominal pain, which progresses to nausea, vomiting, and often diarrhea as the attack evolves.10 Some patients report the onset of nausea hours before the onset of a full-blown attack.11 During an attack, the abdomen is usually tender to the touch.10 Thus, this type of attack can be difficult to distinguish from a surgical emergency, and it is estimated that approximately one-third of patients with undiagnosed HAE undergo unnecessary surgery.7 Yet even if untreated, symptoms usually subside within several days.7,10
Incidence and predilection (if any) for race, gender, ethnicity
While urticaria and angioedema are common problems, affecting nearly 20% of the population, HAE is a rare disorder, accounting for only 2% of clinical angioedema cases.12
HAE affects all ethnic groups, with no recognizable racial predilection. And as an autosomal-dominant inheritable genetic disorder, neither sex predominates.1,10
1 in 10,000
to 1 in 50,000
Including clinical and laboratory findings associated with angioedema of various causes
HAE symptoms can mimic those of several common conditions, such as allergic reaction.
When a family history is not available, initial misdiagnosis commonly occurs. These patients can be subjected to non-essential medical procedures, ineffective treatments, and/or unnecessary psychiatric referrals (due to “unexplained” recurrent abdominal pain).1,10
Blood tests for C4, C1-INH
When HAE is suspected, patients should have serum levels of C4 measured. A low serum C4 level is an excellent screening test since C4 levels are invariably low in untreated patients with either type I or type II HAE. Antigenic C1-INH levels should also be tested in these patients.13
*Low C1q concentrations occur in some patients with HAE.
Abbreviation: ACE, angiotensin-converting enzyme. Chart adapted with permission from Weiler CR, et al. Mayo Clinic Proc. 2006;81(7):958-972.
Patients who answer “yes” to all or most of the questions may require further workup for HAE.
HAE can be complex to manage and may involve algorithms for both prophylaxis and acute treatment.View the treatment guidelines
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