Hereditary Angioedema

Not actual patients.

Hereditary angioedema (HAE) is an autosomal dominant genetic disease characterized by recurrent attacks of localized subcutaneous and mucosal swelling.^1,2

Angioedema attacks most commonly affect the face, extremities, abdomen and urogenital area and are often painful and debilitating.^1,2

Less commonly, they can occur in the laryngeal area causing airway obstruction and potentially becoming life-threatening.²

Epidemiology

HAE is a rare condition with an estimated prevalence of 1 in 50,000, though exact prevalence may vary due to misdiagnosis and geographical region.^1,2,3 Symptoms are unpredictable and can manifest at any age, but typically appear during childhood (5 to 11 years), worsen during puberty (particularly among females), and persist throughout life.^2,4,5,6,7

Pathophysiology

HAE is an autosomal dominant disorder resulting from a deficiency of C1 inhibitor (C1-INH), which is a naturally occurring protein that inhibits plasma kallikrein, a key mediator of inflammation.^1,8,9,10,11C1-INH deficiency results in uncontrolled kallikrein activity, leading to increased generation of the vasoactive peptide bradykinin and associated symptoms of pain and swelling.^8,9,10,11,12

The disease is marked by its genetic variability – more than 510 different mutations of the C1-INH gene (SERPING1) have been identified.¹³ However, it is generally classified into 3 types according to the underlying cause and levels of C1-INH:

Type I (~85% of cases) is associated with low plasma levels of the C1-INH protein^2,14,15
Type II (~15% of cases) is associated with a dysfunctional C1-INH protein despite normal plasma levels^2,14,15
HAE with normal C1-inhibitor levels (formerly type III, estrogen-dependent) is very rare and is associated with normal C1-INH levels and function but has been linked to a number of other mutations^2,14,15

Diagnosis

Due to its rarity and symptom overlap with other conditions, HAE is frequently under-recognized leading to delayed diagnosis.^4,7,16,17 Historically, the rate of mortality has been higher in undiagnosed HAE patients due to lack of awareness of potential fatal laryngeal attacks and inadequate treatment.¹⁸ The two most common forms of HAE (types I/II) should be suspected when a patient presents with a history of recurrent angioedema attacks and further substantiated by:¹⁹

Positive family history (may be absent in 25% of cases)
Onset of symptoms in childhood/adolescence
Recurrent and painful abdominal symptoms
Occurrence of upper airway edema
Failure to respond to antihistamines, glucocorticoids, or epinephrine
Presence of prodromal signs/symptoms before swellings
Absence of urticaria (wheals/hives)

To confirm diagnosis, patients should be assessed for blood levels of C1-INH protein, C4 and C1-INH function.¹⁹

Navigating HAE

The condition is associated with a substantial and multifaceted burden of illness affecting various aspects of a patient's quality of life (e.g., emotional state, career and education progression, and the decision to have children).^{2,7,20,21,22,23,24} Types I/II are indistinguishable in their clinical presentation, having identical symptoms characterized by edema attacks that can vary in location, frequency, duration, and severity.^1,25,26 Swelling and other symptoms gradually worsen over 12 to 36 hours, intensifying in a relentless manner, sometimes spreading to other sites, and then resolving over 2 to 5 days.^7,14,27

A variety of possible triggers for attacks have been proposed, most commonly mechanical trauma, mental stress, and airway infection.^2,4,28Nevertheless, many attacks occur without an obvious trigger, particularly in children, highlighting the need for individualized treatment plans.^2,4,19

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Hereditary Angioedema