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Severity of Hereditary Angioedema, Prevalence, and Diagnostic Considerations
Jonathan A. Bernstein, MD
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Severity of Hereditary Angioedema, Prevalence, and Diagnostic Considerations

Jonathan A. Bernstein, MD
Hereditary angioedema (HAE) is a rare disorder, characterized by intermittent attacks of swelling in any part of the body, without the presence of hives. This lifelong disease typically presents in the first 2 decades of life, and is commonly associated with a deficiency in functional C1 esterase inhibitor (C1-INH) activity. C1-INH levels may be decreased or normal, with an accompanied decrease in functionality, depending on the type of HAE present. The frequency and severity of attacks are highly variable among patients with HAE, but can have a significant impact on a patient’s quality of life, and may be fatal if not properly managed. Early diagnosis of the disease can lead to the development of an individualized treatment plan to assist with prevention and management of angiodema attacks. Delays in diagnosis remain, as healthcare professionals often fail to include HAE in the differential diagnosis when patients present with attacks, and patients therefore often go undiagnosed or are misdiagnosed for several years before a diagnosis of HAE is made. It is important for providers to recognize the most common clinical features of HAE and how to evaluate patients to effectively diagnose, prevent, and treat future attacks.
Am J Manag Care. 2018;24:-S0
Hereditary angioedema (HAE) is a rare but potentially life-threatening disease affecting approximately 1 in 67,000 individuals, with no identified differences in prevalence due to sex or ethnicity.1,2 There is a genetic component of autosomal dominant inheritance in approximately 75% of patients, while 25% of patients present with a spontaneous mutation and therefore no evident family history of disease.3,4 Most patients begin to see initial symptoms in the first or second decade of life (mean age of onset is approximately 11 years), with symptoms persisting throughout their lifetimes.5,6 The disease commonly presents with recurrent attacks of swelling in any part of the body, without hives present.7 The pathophysiology generally involves a sudden increase in skin and submucosa vessel wall permeability mediated by excessive bradykinin, leading to extravasation of plasma and subsequent swelling in the tissue.8

Types of Hereditary Angioedema

Hereditary angioedema is most commonly associated with a quantitative or qualitative deficiency in C1 esterase inhibitor (C1-INH), due to a mutation in the C1-INH SERPING1 gene, located on chromosome 11q.8 C1-INH is a key inhibitor of 3 enzymes in the kallikrein-kinin cascade: factor XIIa, factor XIIf, and plasma kallikrein. Loss of functionality of C1-INH results in activation of the entire cascade and most notably excessive cleavage of high-molecular-weight kininogen, leading to increased bradykinin production. Bradykinin is a peptide that binds to the bradykinin B2 receptor on vascular endothelial cells. The binding of bradykinin to its receptors induces vasodilation and increased endothelial permeability.8 This increase in bradykinin levels leads to increased vascular permeability, which results in the classic symptoms of localized swelling and inflammation.2,8

Deficiency of functional C1-INH activity is an autosomal dominant genetic disorder that can be further classified into 2 types. Type I HAE, which accounts for approximately 85% of cases, occurs due to a genetic mutation leading to a reduced quantity of secreted functional C1-INH.1,7 In type II HAE, which occurs in approximately 15% of patients, the C1-INH is present in normal to elevated quantities but is dysfunctional and therefore unable to inhibit target proteases.1,7

More recently, HAE has been identified in patients who present with normal C1-INH levels and activity, classified as HAE with normal C1-INH (previously known as type III HAE).9 Symptoms of HAE-normal C1-INH appear to be estrogen sensitive and therefore frequently identified in women.9 HAE-normal C1-INH can further be divided into HAE due to mutations in the factor XII gene (HAE-FXII), plasminogen (HAE-PLG), angiopoetin-1 (HAE-AGPT1), or an unknown genetic cause (HAE-unknown).9

Clinical Presentation

Symptoms of HAE often begin during childhood or adolescence, worsen around puberty, and persist throughout a patient’s lifetime.4,6 A retrospective analysis conducted by Bork and colleagues found a mean age of onset of symptoms of 11.2 years, with approximately 50% of patients experiencing their first attack before age 10 years.6

The severity and frequency of swelling in patients with HAE is highly variable.7 Swelling is characteristically episodic rather than continuous, with many patients experiencing swelling episodes every 10 to 20 days if not treated.4 However, when examining individual patient experiences, the incidence of swelling can vary from more than 1 swelling per week to fewer than 1 per year.10,11 The frequency and severity of attacks also varies considerably in affected families with the same C1 inhibitor mutation.6,10,12

Hereditary angioedema typically presents as recurrent episodes of nonpitting, nonpruritic edema affecting 3 main areas: subcutaneous tissue (face, upper or lower extremities, genitals), abdominal organs (stomach, intestines, bladder), and the upper airway (larynx, tongue).7,13 The most frequent sites of swelling include the skin (100%), the abdomen (97%), and the larynx (54%), although any of the above sites alone or in combination may also be involved.6

Subcutaneous attacks typically progress and evolve over several hours, last for approximately 2 to 4 days if untreated, and are described as a nonpruritic, nonerythematous, and circumscribed swelling of the skin, as seen in Figure 1.12-14 The swelling is not typically accompanied by urticaria, as would be seen with allergic angioedema, and is most commonly seen in the upper and lower extremities, with the upper extremities most often affected.6,13 Approximately one-third of attacks may be preceded by erythema marginatum, which is a nonpruritic, serpiginous rash producing a map-like pattern on the skin.1,15 It occurs more often in children, and is often mistaken for similar rashes that accompany childhood viral or bacterial illnesses, or is misdiagnosed as urticaria.15 Subcutaneous angioedema typically resolves spontaneously but causes substantial disability.13

Abdominal attacks in HAE are caused by transient edema of the bowel wall, with clinical symptoms including diffuse continuous pain, vomiting, diarrhea, and abdominal cramping.10,13,16 Cases of hypovolemic shock resulting from fluid loss, plasma extravasation, and vasodilation have been reported in severe attacks.10 Notably, there is usually no fever, which can be an important diagnostic indicator.13 Recurrent abdominal pain has been reported to occur in 70% to 90% of patients diagnosed with HAE.6,17 Attacks are often preceded by a prephase composed of nonspecific symptoms, such as irritability, aggressiveness, fatigue, or hunger.16 Symptoms of an abdominal attack in HAE mimic those of acute abdominal emergencies, such as acute appendicitis, mesenteric lymphadenitis, and intussusception, and patients often undergo unnecessary emergency surgery.12,15,17 In 1 study, 34% of patients with HAE had been misdiagnosed during an abdominal attack and underwent an appendectomy, exploratory laparotomy, or both.10 Abdominal ultrasound and computerized axial tomography scan can help with the differential diagnosis in these patients by detecting free peritoneal fluid, edematous intestinal mucosa, and abnormalities in liver structure; however, these are not clearly specific for angioedema.15,17 Symptoms in an abdominal attack typically spontaneously subside within 24 hours of peak symptom expression, with a total time from presentation to resolution of approximately 2 to 5 days.10,12

Angioedema of the upper airway is a less common, although potentially life-threatening, site of attack in patients with HAE. Although less than 1% of all swelling attacks involve the larynx, approximately 50% of all patients with HAE have a laryngeal attack at some point in their lifetime.6,17 Laryngeal edema can be fatal because of the risk of potential suffocation without alleviation of symptoms and is a significant cause of death in patients with HAE.16,18 Before the availability of specific treatment agents for patients with HAE, mortality associated with laryngeal edema was approximately 30%.17 Laryngeal edema typically occurs later in life than other types of swelling in HAE, with results of 1 study finding the mean age of first laryngeal edema to be 26.2 years, with nearly 80% of laryngeal edemas occurring between 11 and 45 years.18 Pediatric patients represent a significant challenge in the diagnosis of laryngeal edema. Timely diagnosis in a pediatric patient is critical because asphyxiation in a pediatric patient presenting with angioedema can happen quickly, due to their smaller airway diameter.15 An important diagnostic differentiation is that standard medications used to treat acute airway edema in children (antihistamines, corticosteroids, and epinephrine) are ineffective in laryngeal edema attacks in HAE.15

Clinical symptoms of laryngeal edema include hoarseness, stridor, dyspnea, dysphagia, voice changes, and a globus sensation.6,13 In some patients, these symptoms may be accompanied by swelling of the soft palate, including the uvula and tongue.6,18 The time from onset of laryngeal edema to maximum swelling has been reported to range from 8 to 12 hours, but may be considerably shorter or longer.18

Less common manifestations of HAE include neurologic, pulmonary, renal, urinary, and musculoskeletal symptoms.6 Edema has also been noted in the soft palate, uvula, and tongue, both separately and in conjunction with laryngeal edema. Severe headaches accompanied by other neurologic symptoms, such as vision disturbances, impaired balance, and disorientation, have also been reported. Recurrent pulmonary and esophageal symptoms have been documented, including chest pain, shortness of breath, and severe pain while swallowing food. Urinary symptoms of HAE include urinary retention, bladder spasm, anuria, or pain at micturition. Pain and swelling of the shoulder and hip joints, and muscles of the neck, back, and arms have also less commonly been reported in patients with HAE.6

A number of potential attack triggers have been proposed with HAE; the well-recognized triggers include minor physical trauma, prolonged sitting or standing, exposure to certain foods, medications (especially angiotensin-converting enzyme [ACE] inhibitors), estrogen-containing contraceptives, and hormone replacement therapies), chemicals, surgery, infection, and emotional/psychological stress.4,6,17 Results of a recent study by Caballero and colleagues showed that of the 395 patients who reported having attacks related to HAE, 42.5% of these patients reported an identifiable trigger. The most common triggers associated with attacks included emotional distress, followed by physical trauma and infection.19 However, many attacks occur without the presence of an identified trigger; the same trigger may not always provoke an attack in an individual patient; and triggers may change for an individual patient over time.1,4 Known triggers do not seem to directly result in swelling, but rather reduce the threshold for the initiation of an attack.12

Epidemiology and Financial Burden

Despite the often-reversible nature of HAE attacks, their unpredictability and often association with stressful circumstances lead to increased difficulties for patients, their families, and employers.12 As with other diseases that are characterized by acute attacks, such as asthma, the burden of HAE is not only economic but also impacts the patient’s quality of life, education, relationships, and career.20 

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