TIP: The World Allergy Organization recommends that all children of a parent with HAE be tested.

Pathophysiology

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

Sources of C1-INH3
  • Hepatocytes (primary)
  • Peripheral blood monocytes
  • Microglial cells
  • Fibroblasts
  • Endothelial cells
Additional factors suspected of triggering and maintaining angioedema3,4
  • XIIa
  • Kallikrein
  • Plasmin

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

Types of HAE

3 types, characterized by plasma levels and functionality of the C1-INH protein

The variants of HAE related to C1-INH function are:

  • Type I: affecting approximately 85% of those with HAE and characterized by low antigenic and functional plasma levels of a normal C1-INH protein2
  • Type II: affecting approximately 15% of those with HAE and characterized by the presence of normal antigenic levels with low level of function due to the dysfunctional mutant protein2
  • HAE with normal functioning C1-INH (formerly called type Ill): affecting mostly female patients and characterized by normal functional levels of C1-INH5

Acquired angioedema (AAE) is very rare and is due to immune complexes that are usually linked to an underlying lymphoproliferative disorder.5

Type I2

Low level
of C1-INH

C1-INH functions
normally

Occurs equally in
men and women

The most common:
~85% of people
with HAE

Type II2

Normal level
of C1-INH

C1-INH does not
function normally

Occurs equally in
men and women

~15% of people
with HAE

HAE with normal
functioning C1-INH2 (formerly known as type III)

Normal level
of C1-INH

C1-INH functions
normally

More common in
women than men

Extremely rare

Not well understood:
C1-INH lab tests are normal but a person still has symptoms of HAE

Symptoms

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:

  • Nausea/abdominal cramping
  • Fatigue, muscle aching
  • Rash (erythema marginatum-like)
  • Numbness/tingling

Progression:

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.

Prodromal symptoms of laryngeal attack9
  • Hoarse voice
  • Dysphagia
  • Feelings of tightness

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

Etiology and Prevalence

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

Global HAE incidence
globe

1 in 10,000
to 1 in 50,000
persons11

Diagnosis

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

Edema of HAE does NOT respond to2:
  • Epinephrine
  • Antihistamines
  • Glucocorticoids

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

Clinical and laboratory findings associated with angioedema of various causes2

C4 level
Antigenic C1-INH level
Functional C1-INH level
C1q level
Type I
Low
Low
Low
Normal*
Type II
Low
Normal or high
Low
Normal
HAE with normal C1-INH (formerly known as type III)
Normal
Normal
Normal
Normal
Acquired C1-INH deficiency
Low
Low (type I) Normal or low (type II)
Low
Low
ACE inhibitor–induced angioedema
Normal
Normal
Normal
Normal
Idiopathic angioedema
Normal
Normal
Normal
Normal

*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.

8 simple questions to differentiate HAE from other angioedema9

Patients who answer “yes” to all or most of the questions may require further workup for HAE.

  1. Unexplained edema?
  2. Asymmetric swelling attacks to the extremities?
  3. Unexplained abdominal pain?
  4. Recurrent attacks?
  5. Family history of similar episodes?
  6. Symptoms (eg, tingling or nausea) signaling the onset of an attack?6
  7. Antihistamines, epinephrine, or corticosteroids provide little relief?2
  8. Angioedema without urticaria?

Clinical management of 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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