Pathogenesis and laboratory diagnosis of hereditary angioedema

Hereditary angioedema (HAE) was first described in the 19th century. Over the past 50 years, many details of the pathophysiology and molecular biology of HAE have been elucidated. Two types of HAE, type I and type II, result from mutations in the gene for the broad-spectrum protease inhibitor C1 inhibitor (C1INH). Type I HAE is characterized by low antigenic and functional C1INH levels and type II HAE has normal antigenic but low functional C1INH levels. Type III HAE, by contrast, has normal antigenic and functional C1INH levels. In some families, type III HAE has been linked to mutations in Hageman factor. C1INH is the primary inhibitor of the complement proteases C1r and C1s as well as the contact system proteases activated Hageman factor (coagulation factor XIIa and XIIf) and plasma kallikrein. It is also an inhibitor of plasmin and coagulation factor XIa. The primary mediator of swelling in HAE has now been unequivocally shown to be bradykinin, generated from activation of the plasma contact system. The knowledge gained concerning the underlying mechanisms of the different types of HAE allow the clinician to approach the laboratory diagnosis with confidence and provides opportunities for novel therapeutic strategies.