Hereditary Angioedema 

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. 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. Type II HAE is characterized by the presence of normal or elevated levels of a dysfunctional C1-INH. Type III HAE has been recently identified as an estrogen-dependent inherited form of angioedema occurring mainly in women with normal functional and quantitative levels of C1-INH.

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^[1] or kallikrein inhibitor or, if those are unavailable, fresh-frozen plasma. In HAE type III, infusion of C1-INH has proven to be ineffective. (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.

C1-INH is a member of the serpin family of protease inhibitors, as are alpha-antitrypsin, antithrombin III, and angiotensinogen.^[2] 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 factor I) can halt the cascade.

Evidence is now overwhelming that bradykinin is the mediator responsible for capillary leakage.^[2] 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.^[3] 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 in clinical trials is reported to rapidly terminate attacks.

Other kinins may also be pathogenic. The inciting factor responsible for inducing the release of these vasoactive peptides is unclear. Factor XII activation may be secondary to a genetic mutation or phospholipid release from damaged or apoptotic cells and may be important in the generation of bradykinin from endothelial activation.^[4] This hypothesis encompasses the role of illness or tissue injury in the generation of bradykinin.^{[5, 6]}

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 150 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.^[3] Half the normal level of C1-INH is believed to be insufficient to prevent attacks of angioedema.

Type II HAE is caused by mutations that involve the active site of exon 8. These mutations result in a dysfunctional protein.^[3] 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 type III HAE, 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. 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 allow for the inappropriate activation of the kinin cascade.^[7]

Two genetic types of HAE result in essentially the same phenotypic expression.^[8] The C1 inhibitor (C1-INH) gene is located on chromosome 11 in the p11-q13 region. Restriction endonuclease techniques demonstrate that multiple mutations can result in the affected phenotype. The inheritance is autosomal dominant with incomplete penetrance. Those who inherit the abnormal gene can have a clinical spectrum ranging from asymptomatic to severely affected.

Type 1 is the most common form and accounts for approximately 85% of cases. Synthesis or secretion of C1-INH is blocked at the site of the faulty allele but occurs at the normal allele. The result is transcription of the normal protein, yielding quantitative serum concentrations of C1-INH that are approximately 10-40% of normal.

Type 2 HAE accounts for approximately 15% of cases. Because of a mutation near the active site of the inhibitor, nonfunctional C1-INH is synthesized by the abnormal gene. The normal gene appears to synthesize near-normal levels of the inhibitor protein. Whereas patients with type I HAE have depressed serum levels of C1-INH, patients with type II HAE have either normal or increased concentrations of the protein.

A clinical syndrome resembling HAE, termed type 3 HAE, has been described; it affects mainly women.^[9] In this condition, no abnormalities of complement or of C1-INH have been described. Although the data are incomplete, about one third of patients are reported to have functional mutations in the factor XII gene. This is thought to lead to increased activation of the kinin-generating system.

Hormonal fluctuations play a role in HAE, and the surges that occur during adolescence are associated with the usual presentation of the disease at that age. Women often have attacks during menses, but attacks may be less frequent in some patients during the later stages of pregnancy. Both estrogen and antiandrogen therapy have been described as precipitators of attacks.

In most cases, the cause of the attack is unknown. In some cases, trauma precipitates attacks; some patients note that emotional stress precipitates attacks.

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.^[10] 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.^[10] HAE type III was initially thought to occur only in women, but recent family studies have described males with HAE and normal C1 inhibitor levels. Nevertheless, HAE type III 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.^[11] Patients typically experience minor swelling in childhood that may go unnoticed, with increased severity around puberty. However, type III HAE is found in the second decade of life or later and occurs only rarely before puberty.^[7]

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.

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.^[10]

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.

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.