Excerpt from Angioedema, Hereditary

Synonyms, Key Words, and Related Terms: hereditary angioedema, HAE, C1-INH, C1 inhibitor, swelling of the skin

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Background: Hereditary angioedema (HAE) is an autosomal dominant disorder of C1 inhibitor (C1-INH) deficiency manifested by painless, nonpruritic, nonpitting, swelling of the skin. 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 exclusively in women with normal functional and quantitative levels of C1-INH.

Pathophysiology: The gene for C1-INH has been mapped to 11q12-q13.1. C1-INH is a multifunctional serine protease inhibitor that is normally present in high concentrations in plasma. It is the only known plasma inhibitor of C1r and C1s, the activated proteases of the first component of complement. It is also the major plasma inhibitor of activated Hageman factor, the first protease in the contact system. Additionally, C1-INH is one of the major inhibitors of plasma kallikrein, the contact system protease that cleaves kininogen and releases bradykinin.

Presumably, uncontrolled activation of the contact system allows for the release of kininlike mediators, resulting in edema of subcutaneous or submucosal tissues. Although the issue of which vasoactive peptide is ultimately responsible for these changes remains controversial, direct evidence supports the importance of bradykinin in the clinical presentation of angioedema. Other kinins may also be pathogenic. The inciting factor responsible for inducing the release of these vasoactive peptides is unclear. Factor XII (Hageman factor) activation may be secondary to phospholipid release from damaged or apoptotic cells and may important in the generation of bradykinin from endothelial activation. This hypothesis encompasses the role of illness or tissue injury in the generation of bradykinin.

HAE is due to mutations within the C1-INH gene and is transmitted as an autosomal dominant trait. 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 characterized by low antigenic and functional plasma levels of a normal C1-INH protein. Type II HAE is characterized by the presence of 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. One theory suggests that estrogen plays a role in up-regulating the production of bradykinin and decreasing its degradation by ACE.

Frequency:

Internationally: HAE is estimated to occur in 1 in 50,000-150,000 individuals.

Mortality/Morbidity: Mortality rates are estimated at 15-33%, resulting from laryngeal edema.

Race: All races are affected, with no reported bias in different ethnic groups.

Sex: Men and women are equally affected.

Age: C1-INH deficiency is present at birth, although only a few patients have been reported with perinatal angioedema. Symptoms usually become apparent in the first or second decade of life. Patients typically experience minor swelling in childhood that may go unnoticed, with increased severity around puberty. HAE is a lifelong affliction, although some report decreased symptoms with age. Five percent of adults with HAE are asymptomatic while carrying the C1-INH mutation, and they are only identified after their children are found to be symptomatic.