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Overview of Epidemiology, Pathophysiology, and Disease Progression in Hereditary Angioedema
William R. Lumry, MD
Management and Prevention of Hereditary Angioedema Attacks
William R. Lumry, MD
Participating Faculty: Hereditary Angioedema: Facilitating Diagnosis and Optimizing Clinical and Economic Outcomes
Hereditary Angioedema: Facilitating Diagnosis and Optimizing Clinical and Economic Outcomes

Overview of Epidemiology, Pathophysiology, and Disease Progression in Hereditary Angioedema

William R. Lumry, MD
Abdominal Symptoms. Recurrent abdominal pain resulting from edema of the gastrointestinal wall is reported in 70% to more than 90% of patients with HAE.14,19 Symptoms can range from mild, intermittent abdominal discomfort to severe colicky pain accompanied by vomiting and/or diarrhea. Cases of hypovolemic shock resulting from fluid loss, plasma extravasation, and vasodilation have been reported in severe abdominal attacks.14 Abdominal episodes of HAE can mimic a number of other conditions, including gastroenteritis, acute appendicitis, mesenteric lymphadentitis, and intussusception, among several less common conditions, which can lead to unnecessary emergency abdominal surgery.14,20 Abdominal ultrasound and computer-assisted tomography scans help with the differential diagnosis by detecting free peritoneal fluid, edematous intestinal mucosa, and liver structure abnormalities, but these signs are not clearly specific for angioedema. 14,20 Hemoconcentration and leukocytosis are sometimes seen in association with abdominal HAE attacks.14,23

Laryngeal Edema. Laryngeal edema is a rare but potentially fatal clinical manifestation of HAE. While less than 1% of all swelling episodes involve the larynx, approximately half of all patients with HAE have a laryngeal attack at some point in their lives.14,19 Before the availability of agents to specifically treat HAE, mortality associated with laryngeal edema was approximately 30%.14 Data from 123 patients suggested that, on average, patients experienced their first episode of laryngeal edema at a later age (26.2 years) compared with their first skin swelling (15.4 years) or abdominal pain attack (16.2 years).4 However, laryngeal edema has been reported in patients as young as 3 years.4 Pediatric patients present a particular diagnostic challenge because laryngeal edema may be misdiagnosed as allergic asthma or epiglottitis.20 Further, compared with adults, asphyxiation in children may develop more quickly due to their smaller airway diameter.20 An important diagnostic clue is that standard medications (ie, antihistamines, corticosteroids, and epinephrine) normally effective for alleviating acute airway edema in children are generally ineffective for laryngeal HAE attacks.20

Clinical symptoms of laryngeal edema include voice changes (eg, hoarseness or deepening of the voice), a feeling of tightness or a lump in the throat, and dysphagia.4,19 Patients with advanced swelling often have aphonia (ie, loss of voice) and fear of asphyxiation with substantial anxiety. Upper airway obstruction is usually caused by laryngeal and glottal edema.4 In some patients, laryngeal edema may be accompanied by swelling of the soft palate, including the uvula and the tongue.19 The time from onset of laryngeal edema to maximal swelling has been reported to range from 8 to 12 hours, but may be shorter or considerably longer.4 Local trauma, such as dental work, endoscopy, and intubation during general anesthesia, has been reported to trigger laryngeal swelling in some patients with HAE.4

Other Symptoms. Less common but clinically important manifestations of HAE may include neurological, pulmonary, renal, urinary, and musculoskeletal symptoms, many of these having been only recently identified.19 As mentioned, edema of the soft palate, uvula, and, rarely, the tongue has occurred, both separately and in conjunction with laryngeal edema. Severe headache accompanied by other neurological symptoms, such as vision disturbances, impaired balance, and disorientation, has recently been reported in patients with HAE.19 Recurrent pulmonary and esophageal symptoms have been documented in a number of patients, including chest pain, shortness of breath, and severe pain while swallowing food.19 Because the symptoms resolved relatively rapidly after administration of C1INH concentrate, they were suggestive of an underlying HAE etiology rather than a surgical emergency. Pulmonary involvement in HAE is controversial and the underlying pathology is not well understood.14,19 Urinary symptoms of HAE may include difficulty of urination, pain while urinating, and bladder spasm. Pain and swelling of the shoulder and hip joints and muscles of the neck, back, and arms has been reported in some patients.19

Diagnosing Hereditary Angioedema

Early detection and diagnosis of HAE before the onset of clinical symptoms is critical for appropriate treatment, preserving patients’ quality of life, and because even the first attack of laryngeal edema can be fatal. Despite advances in testing procedures and more disease recognition, the diagnosis of HAE still presents considerable challenges for physicians, particularly in the primary care setting. Diagnosis is made through a careful evaluation of clinical symptoms and family history, and confirmed using laboratory testing (Figure 3). Clinical symptoms of recurrent abdominal pain or edema in the absence of associated urticaria should prompt suspicion of HAE, particularly in patients with a positive family history. The absence of a family history, however, is not a disqualifying feature, since up to 25% of HAE patients have spontaneous C1INH mutations.24,25

Laboratory Findings. Laboratory tests provide the definitive diagnosis of HAE. Measurement of plasma levels of complement factor 4 (C4) and C1INH is the first step in the diagnostic algorithm, as shown in Figure 3. Virtually all patients with HAE have persistent low levels of antigenic C4, although about 2% of patients have been reported to have normal C4 levels between edema attacks.1,25 Measurement of C4 is generally considered a valuable, cost-effective test for HAE in patients with unexplained recurrent edema because normal C4 levels, particularly at the time of a swelling episode, almost always indicate an alternate etiology.5 Some clinicians, however, advocate testing for C1INH regardless of C4 levels to avoid possible false negatives—1 study of diagnostic assays for HAE reported a sensitivity of low C4 of just 81%.26 Despite the best available evidence, 1 recent survey of US allergists/immunologists and primary care physicians who treat HAE found that only 64% of respondents used C4 testing to aid in the diagnosis of HAE.5 Almost 84% reported that they used C1INH level and function testing.5

Low levels of both C4 and antigenic C1INH indicate a diagnosis of type I HAE, which should be confirmed with repeat testing.25 In cases where there is a strong clinical suspicion of HAE in the context of a low-to-normal C4 test and normal levels of antigenic C1INH, a functional C1INH assay should be obtained.26 Functional C1INH is a specialized test and should be obtained from an experienced laboratory to avoid sample mishandling or misinterpretation.25 A normal C4 and functional C1INH result rules out both type I and type II HAE, but does not rule out HAE with normal C1INH.25 At this point, there is no validated assay for diagnosing this type of HAE. A minority of patients with this form of the disease have mutations in genes encoding coagulation factor XII13; testing for this mutation may have some utility in women with recurrent, unexplained edema and an established family history of HAE.13,25

Prenatal and Postnatal Diagnosis. As HAE is a genetic disorder transmitted in an autosomal dominant fashion, the offspring of a parent with HAE have a 50% chance of inheriting the disease.20 Prenatal genetic testing for HAE is requested rarely and is only indicated if the mutation of the affected parent is known.27 Material for genetic testing is obtained from a chorionic villus sample after 10 weeks or amniocentesis after 15 weeks.20,27 It is generally considered impractical to test for HAE in the prenatal setting because a mutation is not always detected, the same mutation may be associated with different phenotypes, and the severity of the disease is not predictable.20

For infants with an affected parent, testing for antigenic and functional C1INH is first performed at the age of 6 months or later, when complement levels typically reach adult values.20 As false positive or false negative C1INH results can occur in infants under 1 year of age, repeat testing at a later age (usually at 1 year) is indicated to confirm the diagnosis.20,28 C4 levels typically reach adult values between the ages of 2 and 3 years.27 Genetic testing can be useful for establishing a diagnosis of HAE in asymptomatic children for whom C1INH and C4 assay results are equivocal.20

Diagnosis of HAE in symptomatic children may be impeded by a negative family history, resulting in misdiagnosis. Conversely, a diagnosis of HAE in children has sometimes led to screening and identification of the disorder in a previously undiagnosed parent.20

Delayed Diagnosis of HAE—A Persistent Problem With Serious Consequences. Diagnostic delays in patients with HAE have decreased substantially over the past few decades—in 1976 the average time to diagnosis from onset of symptoms was reported to be 21 years.29 Even today, however, the majority of US physicians estimate that most patients experience symptoms for an average of 7 years before a definitive diagnosis is made,30 and a few patients completely slip through the cracks. A recent case report from Texas described a 57-year-old man with previously undiagnosed HAE who started experiencing symptoms in his teens—a diagnostic delay of about 40 years.31 While this case is clearly an outlier, in the Spanish HAE registry study from 2005, the average time to diagnosis from symptom onset was still more than 10 years.6 A web-based survey of US physicians conducted in 2009 to 2010—The Surveillance Project on Hereditary Edema—reported an average time to diagnosis ranging from 0 to 6 months (5.8%) to more than 10 years (5.8%).30 Less than 38% of patients with HAE were diagnosed within 1 to 3 years from the first appearance of symptoms.30

As mentioned, delays in the diagnosis of HAE can have serious consequences, including impaired quality of life, lost productivity and income, depression, unnecessary and/or inappropriate medical procedures, and more frequent utilization of health resources leading to increased healthcare costs.31,32 An online survey of 63 patients with HAE conducted in 2004 found that patients averaged 4.7 emergency department (ED) visits each year; nearly 21% received treatment for anaphylaxis in the ED.32 Unnecessary abdominal surgery was not uncommon in patients with undiagnosed HAE, particularly if severe abdominal pain was the presenting or predominant symptom.33 Appendectomy and exploratory diagnostic procedures, such as colonoscopy, were common procedures.33


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