Abstract
Hereditary angioedema (HAE) is a rare genetic condition that manifests as painful and potentially life-threatening episodic attacks of cutaneous and submucosal swelling. It results from functional deficiency of C1 inhibitor (C1 INH), which is a regulator of the complement, fibrinolytic, kinin (contact), and coagulation systems. In patients with HAE, the low plasma concentration of functional C1 INH leads to overactivation of the kinin cascade and local release of bradykinin. Bradykinin is responsible for the pain, vascular permeability changes, and edema associated with HAE. Until recently, therapeutic options for HAE have been very limited. Many new therapies have emerged, however, such as C1 INH replacement drugs and medications aimed at components of the contact system (eg, plasma kallikrein inhibitor and bradykinin B2 receptor antagonist). The authors review current and novel treatments for patients with HAE.
Hereditary angioedema (HAE) is a rare autosomal dominant disorder resulting from deficiency of C1 inhibitor (C1 INH) protein or function. Individuals with HAE undergo “attacks,” or episodic swelling, which most often affect the skin of the extremities or the mucosal tissues of the upper respiratory and gastrointestinal tracts.
The disease is caused by a mutation in the gene-encoding C1 INH protein located on chromosome 11. C1 INH, a serine protease inhibitor (serpin), is a primary regulator of the complement and kinin systems. Deficiency of C1 INH leads to unregulated activation of bradykinin. Data from various studies
1-3 indicate that bradykinin plays an important role in mediating HAE symptoms such as pain and vascular permeability changes that lead to edema.
Two main types of HAE, type I and type II, account for the majority of HAE cases. Type I HAE (found in approximately 80%-85% of patients with HAE) is characterized by low levels of C1 INH. Type II HAE (found in 15%-20% of patients with HAE) is characterized by normal or elevated levels of dysfunctional C1 INH.
4,5 A newer subtype of HAE, type III, has been described within the past decade. In some patients, type III HAE is characterized by X-linked dominant inheritance.
6 It is more common in female individuals, but it has also been identified in male individuals. Both estrogen-dependent and estrogen-independent forms of type III HAE have been described. Type III HAE is not associated with C1 INH deficiency, but it manifests with symptoms similar to those of types I and II. Some cases of type III HAE are associated with genetic defects involving factor XII (Hageman factor).
6 Type I and type II HAE could perhaps more correctly be described as “C1 INH deficiency disease” and are clinically indistinguishable. Once angioedema is clinically suspected, laboratory findings for C4 and C1 INH levels, as well as C1 INH function, can support a specific diagnosis (
Table 1). In the present review, we will focus on types I and II HAE.