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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
The economic burden of HAE was analyzed by Wilson and colleagues, who conducted a survey of 457 patients diagnosed with HAE. They estimated the annual per-patient cost of HAE to be $42,000 for the average patient, with annual costs estimated at $14,000 for patients with mild attacks, $27,000 for patients with moderate attacks, and $96,000 for patients with severe attacks. The cost of hospital care accounted for approximately 67% of direct medical costs. Indirect costs (eg, missed work, lost productivity, lost income) totaled $16,000 for the average patient, with these indirect costs increasing with disease severity.20

Another patient survey conducted by Banerji and colleagues in 186 patients with diagnosed HAE found that 72% of patients with type I or II HAE and 76% with type III HAE reported that HAE had a significant impact of their quality of life.21 A survey of 26 patients with diagnosed HAE found that 39% of patients were identified as experiencing depression of mild (50%), moderate (40%), or severe (10%) levels.22 

Therefore, the effects of HAE spread far beyond the physical effects during a swelling attack and can also lead to significant effects on emotional well-being, negatively impact a patient financially, and lead to a decrease in overall quality of life for a patient and their family.

Diagnosis of Hereditary Angioedema

Early detection and diagnosis of HAE are critical to effectively initiate appropriate patient management and preserve the patient’s quality of life. Despite advances in testing procedures and disease recognition, the diagnosis of HAE still presents a considerable challenge for physicians. Diagnosis should be initiated with a careful evaluation of both clinical symptoms and family history, and confirmed using laboratory testing. Clinical symptoms of recurrent abdominal pain or angioedema in the absence of associated urticaria should trigger suspicion of HAE, particularly in patients with a positive family history.4,7,23

Obtaining a thorough family history is important in patients presenting with angioedema without urticaria. If there is a positive family history of HAE, the diagnosis can be refined by further investigating laboratory values and genetic testing. The absence of family history is not sufficient to rule out HAE because 25% of patients with HAE will present with a spontaneous C1-INH mutation.23,24

Diagnostic confirmation of HAE requires laboratory testing. This testing focuses on an antigenic and functional assessment of C1-INH. Measurement of plasma levels of complement factor 4 (C4) should be the first test performed in a patient presenting with isolated angioedema and no clear family history of angioedema.  However, a clear family history measurement of C4 and C1-INH functional and quantitative levels is the first step in diagnostic evaluation in these patients. (Figure 2).25,26 Nearly all patients with HAE will have persistent low levels of antigenic C4, although approximately 2% to 4% of patients are reported to have normal C4 levels between edema attacks.1,25,27 Measurement of C4 is considered a valuable, cost-effective test for HAE in patients with unexplained recurrent edema because it can be easily measured in most clinical laboratories.7 Although a low C4 is indicative of HAE, normal levels of C4 may not exclude the potential for HAE. Results from a study evaluating C4 diagnostic assays found that the sensitivity of low serum C4 for HAE among untreated patients was 81%, and that normal C4 levels were found on 9 separate occasions in 5 untreated patients with HAE.26 Therefore, C1-INH studies are necessary regardless of C4 levels when there is a high clinical suspicion of HAE.26 

Testing beyond C4 levels also allows for the potential identification of the specific type of HAE in an individual patient (Table 1).28 C1-INH levels and functional assays should be obtained along with the C4 level. The C1-INH functional assay is a specialized laboratory test and should be done only in experienced reference laboratories.25 If both C4 and C1-INH levels are low, and C1-INH functional activity is low, this is consistent with type 1 HAE.25 If C4 levels are low or normal and C1-INH levels are normal, but clinical suspicion of HAE is strong, a C1-INH functional assay can be helpful. Type II HAE will demonstrate a low or normal C4 level, normal C1-INH level, but low C1-INH functional activity.25 If C4 levels, C1-INH levels, and C1-INH functional activity are all normal, HAE-normal C1-INH may be considered (mutations in the coagulation factor XII gene, plasminogen, AGPT-1, or other unknown defects).1,25 It is also important to note that routine blood tests, such as a blood count, electrolytes, and C-reactive protein, are unaffected by C1-INH deficiencies.12

Because HAE is a genetic disorder transmitted in an autosomal dominant fashion, the child of a parent with HAE will have a 50% chance of inheriting the disease.15 For infants of an affected parent, testing for C1-INH levels and functionality can be performed at age 6 months or later, when complement levels are thought to reach adult values.15 As false-positive or false-negative C1-INH results can occur in infants younger than 1 year, repeat testing at a later age is indicated to confirm the diagnosis.13,15 C1-INH level and function appear to be reliable measures in children younger than 12 months, although C4 levels typically reach adult levels between 2 and 3 years, so are not reliable measurements before that time.29,30

Differential Diagnosis

When a patient presents with angioedema in a primary care setting, a thorough clinical examination in addition to laboratory work will assist in differentiating HAE from other potential causes of angioedema (Figure 3).24

Allergic Angioedema
Allergic or mast cell-mediated angioedema occurs as a result of mast cell degranulation, which may be caused by antigen-specific immunoglobulin E (IgE) antibodies to a specific allergen exposure. The most common allergens include food, insect venom, latex, and drugs.7,9 However, many cases of mast cell-mediated angioedema do not have a clear identifiable trigger or cause despite comprehensive evaluation. The resulting release of histamine and other vasoactive mediators produces swelling often but not always associated with urticaria and pruritus.7 Symptoms typically begin within 2 hours of exposure (if an allergen or trigger is involved). It is important to note that, unlike in HAE, the swelling responds to antihistamines, corticosteroids, and epinephrine, because the swelling is mediated by histamine release, unlike the bradykinin-mediated swelling produced in patients with HAE.7

Acquired C1-INH Deficiency

Symptoms of acquired C1-INH deficiency typically resemble those of HAE but do not present until the fourth decade of life or later, and patients will have no associated family history of disease.7,9 It is often associated with other diseases, most commonly B-cell lymphoproliferative disorders.24 In some patients, autoantibodies to C1-INH will develop; this does not preclude the presence of an underlying lymphoproliferative disease.7 Laboratory studies will reveal low C4 and C1-INH levels, as well as low functional activity. Often, C1q levels will also be low, which can be helpful in distinguishing acquired C1-INH deficiency from HAE-C1-INH, because C1q levels are generally normal in HAE. However, C1q can be normal in acquired angioedema (AAE), which can make it difficult to differentiate between HAE occurring as a de nova mutation, as in both situations there is no family history.  In this circumstance, it may be necessary to genotype the patient for a SERPING1 mutation, which will be absent in AAE. Due to the link with autoimmune and malignant disorders, a patient diagnosed with acquired C1-INH deficiency should be evaluated for other underlying diseases.7,24

Drug-induced Angioedema

Drug-induced angioedema is most commonly associated with the use of ACE inhibitors.4,7,9 This type of angioedema most often presents as a well-defined swelling of the tongue, lips, or other parts of the face. Life-threatening airway edema can occur in 25% to 39% of cases.8,31 Angioedema typically occurs within 1 week after starting the medication; however, there have also been reports of angioedema occurring after several months or years of medication use.9,31 Risk factors for the development of ACE inhibitor-induced angioedema include black race, female gender, development of a previous drug-related rash, smoking, age older than 65 years, seasonal allergies, obesity, upper airway surgery or trauma, sleep apnea, and immunosuppressive use.31 The swelling that occurs is not related to histamine release; ACE typically degrades bradykinin, so the inhibition of ACE in these patients leads to an accumulation of bradykinin.7 Treatment consists of discontinuation of the medication. Because this is a class effect, these medications should be discontinued in any patient who develops isolated angioedema.7 Angiotensin II receptor blockers (ARBs) appear to have a much lower incidence of recurrent angioedema and are an option for use in patients with a history of ACE inhibitor-induced angioedema.4,25

If no clear cause of recurrent angioedema can be found, the angioedema is typically labeled as idiopathic.7 Some patients with idiopathic angioedema fail to benefit from high doses of antihistamines, which suggests that a subset of idiopathic angioedema is mediated by bradykinin.7

Delays in Diagnosis of Hereditary Angioedema

Diagnostic delays in patients with HAE have decreased substantially over the past several decades, likely due to a growing awareness in the medical community.7,13 However, substantial delays still exist in the correct identification and management of patients with HAE. The earlier that HAE can be identified, the sooner that patient-centered management can be initiated to prevent and appropriately treat subsequent attacks.7

A Web-based survey of US physicians conducted in 2009-2010 found an average time to diagnosis ranging from 0 to 6 months (5.8%) to more than 10 years (5.8%). Fewer than 38% of physicians reported a time to HAE diagnosis of 1 to 3 years from the onset of symptoms.32 This delay is important because conventional treatments, such as antihistamines and corticosteroids, are ineffective in undiagnosed HAE, and the majority of deaths occur in patients who are undiagnosed.12,33

 
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