Innovations in Hereditary Angioedema Pathophysiology

Hereditary angioedema (HAE) is a rare, inherited disease mostly associated with mutations in the SERPING1 gene (serpin family G member 1), which encodes the C1 inhibitor (C1-INH) protein. Regulation can lead to plasma deficiency and ensuing repeated attacks of severe angioedema. This disease was first described clinically and genetically in 1888 by William Osler, who named it 'hereditary angioneurotic edema (HANE).' It took 75 years until Donaldson and Evans identified the fundamental role of C1-INH in the pathophysiology of so-called HANE by Osler. Significant progress has been made in the research of this genetic disease when the role of neural factors was documented as being too small to lead to edema, the name was changed as HAE. Therefore, the name of more than 490 different mutations have been reported in the region of the C1-INH gene (SERPING1) until mid-2018. It is now known that C1-INH deficiency overstimulates the plasma contact (kallikrein-kinin) system, which eventually results in the overproduction of bradykinin. By binding to the bradykinin B2 receptor, bradykinin increases vascular permeability (vasodilation) and causes contraction of nonvascular smooth muscle, and acts as a main/major mediator in the pathophysiology of HAE. Reports since 2000 have described a new type of HAE with 'normal' CI-INH levels, primarily in Caucasians. A number of abnormalities in the genes encoding for factor XII, angiopoietin-1, and plasminogen have been identified in this novel disease entity. The establishment of treatment modalities for HAE with normal C1-INH is also expected.