Practice Essentials
Although rare, hereditary angioedema (HAE) is associated with episodic attacks of edema formation that can have catastrophic consequences. Laryngeal edema can result in asphyxiation; abdominal angioedema attacks can lead to unnecessary surgery and delay in diagnosis, as well as to narcotic dependence due to severe pain; and cutaneous attacks can be disfiguring and disabling. [1]
Signs and symptoms
Physical signs of HAE include overt, noninflammatory swelling of the skin and mucous membranes. They are referable to the following prominent sites:
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Subcutaneous tissues: Face, hands, arms, legs, genitals, and buttocks
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Abdominal organs: Stomach, intestines, bladder, and urethra; may manifest as vomiting, diarrhea, or paroxysmal colicky pain and can mimic a surgical emergency
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Upper airway (larynx) and tongue: May result in laryngeal edema and upper airway obstruction
In approximately 25% of patients, erythema marginatum may precede the occurrence of edema. [2]
See Clinical Presentation for more detail.
Diagnosis
Complement and genetic testing
The 3 types of HAE can be differentiated with complement testing and, in the case of HAE with normal C1 inhibitor levels, genetic testing. Type I HAE is characterized by the following:
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Low C1 esterase inhibitor (C1-INH) protein level
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Low C4 level
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Normal C1q level
Type II HAE is characterized by the following:
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Normal or elevated, but dysfunctional, C1-INH level
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Low C4 level
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Normal C1q level
HAE with normal C1 inhibitor levels is characterized by the following:
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Normal C1-INH level
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Normal C1-INH functional assay
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Normal C4 and C1q level
Imaging studies
The following imaging studies can be used in the diagnosis of HAE:
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Abdominal radiography: During attacks of gastrointestinal edema, features of ileus may be demonstrated
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Chest radiography: Pleural effusions rarely may be seen
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Abdominal ultrasonography or computed tomography scanning: Edematous thickening of the intestinal wall, a fluid layer around the bowel, and large amounts of free peritoneal fluid may be found
See Workup for more detail.
Management
Agents used in the treatment of acute attacks of HAE include the following:
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C1-INH concentrate: Berinert was approved in September 2009 by the US Food and Drug Administration (FDA) for the treatment of acute abdominal and facial angioedema attacks in adolescents and adults with HAE [5] ; in January 2012, an additional indication for Berinert, for laryngeal angioedema, was approved by the FDA; in July 2014, the FDA approved the recombinant human C1-INH (rhC1-INH) Ruconest to treat acute attacks of HAE in adolescents and adults, although its effectiveness was not established in patients with HAE that involve laryngeal attacks [6, 7]
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Kallikrein inhibitor: During HAE attacks, unregulated plasma kallikrein activity results in excessive bradykinin generation, resulting in swelling; ecallantide (Kalbitor) is a recombinant agent that is a potent, selective, reversible kallikrein inhibitor; the FDA approved ecallantide in December 2009 for treating acute HAE attacks in patients aged 16 years and older [8]
Prophylaxis
The Medical Advisory Board of the HAE Patient's Association has recommended that patients be free to choose their preferred therapy. Prophylactic treatment includes attenuated androgens and the C1 inhibitor protein product Cinryze. If androgen therapy is used dosage should be minimized, balancing disease severity with minimizing adverse effects. The drug most commonly used is danazol, but all attenuated androgens are useful in treatment. The usual recommendation is to try to use 200 mg/day or less.
The nano-filtered C1-INH concentrate Cinryze was approved by the FDA in 2008 for HAE prophylaxis. It is reported to be effective in acute attacks, as well. [11] The first subcutaneous C1-INH concentrate (Haegarda) was approved by the FDA in June 2017 for HAE prophylaxis in adults and adolescents. [12] Lanadelumab, a monoclonal antibody that targets kallikrein, was approved for HAE prophylaxis in August 2018. [13]
See Treatment and Medication for more detail.
Background
Hereditary angioedema (HAE) is an autosomal dominant disease caused by low levels of the plasma protein C1 inhibitor (C1-INH).
Deficiencies in C1-INH allow unchecked activation of the classic complement pathway and other biochemical systems including the bradykinin system. Patients can present with any combination of painless, nonpruritic, nonpitting swelling of the skin (cutaneous angioedema); severe abdominal pain; or acute airway obstruction.
There are 3 types of HAE. Type I HAE is defined by low plasma levels of a normal C1-INH protein reflecting an abnormality of one of the gene alleles of the protein. Type II HAE is characterized by the presence of normal or elevated levels of a dysfunctional C1-INH. Again, one of the two gene alleles is abnormal but here the allele leads to the release of a non-functional protein. HAE with normal C1 inhibitor was identified as an estrogen-dependent inherited form of angioedema occurring mainly in women with normal functional and quantitative levels of C1-INH. There is still no clear understanding of its pathophysiologic mechanism
Prior to the development of effective therapy, the mortality rate from HAE was 20-30%. Although preventable and treatable, the complications of this disease do not respond well to the usual therapies for angioedema; therefore, establishment of the correct diagnosis is critical. The most reliable and cost-effective screening test for HAE is a serum C4 level (see Workup).
Treatment of HAE consists of prophylaxis, management of acute attacks, and prophylactic therapy in situations where attacks may occur. In HAE types I and II, the treatment of choice in acute attacks consists of replacement with commercially available C1 inhibitor (C1-INH) concentrates [14] , a kallikrein inhibitor or a bradykinin receptor type 2 antagonist. If there is no specific treatment available, fresh-frozen plasma has been used, but the physician should understand that, because the plasma may supply the substrate for bradykinin generation, attacks can at times worsen before they improve.
At the time of this report there is no consensus on best therapy for HAE with normal C1 inhibitor (See Treatment.)
For a discussion of acquired angioedema, which is caused by a consumption of C1-INH for any of a number of reasons leading to low levels of this protein, see Acquired Angioedema. For a discussion of angioedema in children, see Pediatric Angioedema. Additionally, go to Angioedema and Emergent Treatment of Angioedema for complete information on these topics.
Pathophysiology
C1-INH is a member of the serpin family of protease inhibitors, as are alpha-antitrypsin, antithrombin III, and angiotensinogen. [15] These proteins stoichiometrically inactivate their target proteases by forming stable, one-to-one complexes with the protein to be inhibited.
Synthesized primarily by hepatocytes, C1-INH is also synthesized by monocytes. The regulation of the protein production is not completely understood but, since patients respond clinically to androgen therapy and demonstrate increased serum levels of C1-INH, it is believed that androgens may stimulate C1-INH synthesis. C1-INH also blocks activation of the lectin pathway by binding to mannose-binding lectin-associated serine proteases (MASPs).
Although named for its action on the first component of complement (C1 esterase), C1-INH also inhibits components of the fibrinolytic, clotting, and kinin pathways. Specifically, C1-INH inactivates plasmin-activated Hageman factor (factor XII), activated factor XI, plasma thromboplastin antecedent (PTA), and kallikrein.
Within the complement system, C1-INH blocks the activation of C1 and the rest of the classic complement pathway by binding to C1r and C1s. Without C1-INH, unchecked activation of C1, C2, and C4 occur before other inhibitors (C4-binding protein and factors H and I) can halt the cascade.
Evidence is now overwhelming that bradykinin is the mediator responsible for capillary leakage. [15] Researchers have demonstrated activation of the kinin system with increased blood bradykinin levels associated with clinical flares. Bradykinin is an important inflammatory mediator formed by the action of the plasma enzyme kallikrein on the substrate high molecular weight kininogen that causes neutrophil chemotaxis, capillary dilation with plasma leakage, and smooth muscle relaxation, and it has been linked to other forms of angioedema.
In an animal model of C1-INH deficiency, bradykinin and bradykinin receptor antagonists prevent capillary leakage. [16] The US Food and Drug Administration has approved the use of a kallikrein enzyme inhibitor for acute treatment, and a bradykinin type 2 receptor antagonist also terminates edema fluid generation and thus terminates attacks.
There is no question that a relatively small subgroup of patients with HAE with normal C1 inhibitor have a factor XII mutation and it is presumed that this mutation is of importance in initiation of attacks. This may be closely related to endothelial cell activation and the initiation of attacks but further research is clearly needed. [17, 18, 19]
Genetics
Hereditary angioedema (HAE) is due to mutations within the C1-INH gene and is transmitted as an autosomal dominant trait. The gene for C1-INH (SERPING1) has been mapped to 11q12-q13.1.
Approximately 300 different genetic mutations have been described in HAE, and a spontaneous mutation rate of 25% has been reported. The 2 variants of HAE related to C1-INH function are type I (85%) and type II (15%).
Type I HAE is caused by mutations occurring throughout the gene, which result in either a truncated or misfolded protein. This protein is not secreted efficiently, resulting in low antigenic and functional plasma levels of a normal C1-INH protein. Even though one normal allele is present, less than 50% of functional C1-INH is present. A possible explanation is that the normal C1-INH protein is down-regulated, and this is supported by the finding of decreased levels of C1-INH mRNA in patients with HAE. [16] Since the C1 inhibitor binds to the protein it inactivates and the complex is removed from the circulation, this may also be responsible for the low levels of C1 inhibitor. Half the normal level of C1-INH is believed to be insufficient to prevent attacks of angioedema.
Most type II HAE is caused by mutations that involve the active site of exon 8. These mutations result in a dysfunctional protein. [16] Therefore, patients with type II HAE have normal or elevated antigenic levels of a dysfunctional mutant protein together with reduced levels of the functional protein. C1-INH deficiency allows autoactivation of C1, with consumption of C4 and C2.
In HAE with normal C1 inhibitor, the C1-INH protein is both qualitatively and functionally normal. The exact mechanism of action responsible for the link between estrogen and angioedema is unclear, thus the term "estrogen-dependent" should be avoided. The illness clearly is seen in males as well but at lower frequency. One theory suggests that estrogen plays a role in up-regulating the production of bradykinin and decreasing its degradation by angiotensin-converting enzyme (ACE).
More recently, mutations in factor XII have been identified in some, but not all patients. These factor XII mutations presumably allow for the inappropriate activation of the kinin cascade. [3]
Epidemiology
Although urticaria and angioedema are common problems that affect nearly 20% of the population, HAE is a rare disorder. It accounts for approximately 2% of clinical angioedema cases and occurs in 1 per 50,000-150,000 population. [1] HAE leads to 15,000-30,000 emergency department visits per year in the United States.
Racial and sexual differences in incidence
Persons of any race can be affected by HAE, with no reported bias in different ethnic groups. Men and women are equally affected for HAE types I and II, although women tend to have more severe attacks. [1] HAE with normal C1 inhibitor levels was initially thought to occur only in women, but recent family studies have described males with HAE and normal C1 inhibitor levels. Nevertheless, HAE with normal C1 inhibitor levels is still thought to predominantly affect women.
Age-related differences in incidence
C1-INH deficiency is present at birth in HAE, although only a few patients have been reported with perinatal angioedema. Symptoms usually become apparent in the first or second decade of life.
Approximately 40% of people with hereditary angioedema (HAE) experience their first episode before age 5 years, and 75% present before age 15 years. [20] Patients typically experience minor swelling in childhood that may go unnoticed, with increased severity around puberty. However, HAE with normal C1 inhibitor levels is found in the second decade of life or later and occurs only rarely before puberty. [3]
HAE is a lifelong affliction, although some report decreased symptoms with age. Five percent of adult HAE carriers are asymptomatic, and they are identified only after their children are found to be symptomatic.
Prognosis
Although rare, HAE is a disease with potentially catastrophic consequences. Laryngeal edema can result in asphyxiation. Abdominal attacks can lead to unnecessary surgery and delay in diagnosis, as well as narcotic dependence due to severe pain. Cutaneous attacks are both disfiguring and disabling, resulting in a diminished quality of life. [1]
HAE patients with an early onset of attacks have a worse prognosis than those with a late onset of attacks.
Prior to the development of effective therapy, the mortality rate was 20-30%. With appropriate use of prophylactic therapy, the prognosis for patients with HAE is now excellent. Judicious use of androgens reduces both short-term and long-term adverse effects. The advent of C1-INH concentrate and kinin pathway inhibitors will greatly enhance the care of these patients.
C1-INH is not needed for intact immune function, and patients with HAE have no increase in the incidence or severity of infections. Other biochemical pathways in which C1-INH is active, such as those for fibrinolysis and clotting, also function relatively normally without normal levels. Unlike other forms of angioedema, histamine is not involved in the pathogenesis of HAE.
Patient Education
Patients should be educated about possible triggering factors of their attacks. They should also be advised of the autosomal dominant inheritance pattern of HAE and that they should anticipate that 50% of their children will be affected. However, phenotypic expression of the condition may vary significantly within families.
For more information on hereditary angioedema (HAE), visit the United States Hereditary Angioedema Association. For patient education information, see the Allergy Center and Skin, Hair, and Nails Center, as well as Hives and Angioedema.
