Hereditary angioedema: Pathogenesis and diagnosis
- Marco Cicardi, MD
Marco Cicardi, MD
- Professor of Medicine
- Università degli Studi di Milano, Italy
- Bruce Zuraw, MD
Bruce Zuraw, MD
- Professor of Medicine
- University of California San Diego
Hereditary angioedema (HAE) is a disease characterized by recurrent episodes of angioedema, without urticaria or pruritus, which most often affect the skin or mucosal tissues of the upper respiratory and gastrointestinal tracts. Although the swelling is self-limited and resolves in two to five days without treatment, laryngeal involvement may cause fatal asphyxiation.
The pathogenesis and diagnosis of hereditary forms of angioedema will be reviewed here. The clinical features, precipitating factors, and treatment of this disorder are discussed elsewhere. (See "Hereditary angioedema: Epidemiology, clinical manifestations, exacerbating factors, and prognosis" and "Hereditary angioedema: Treatment of acute attacks" and "Hereditary angioedema: General care and long-term prophylaxis".)
The swelling (ie, angioedema, sometimes called "giant" swelling) that occurs in hereditary angioedema (HAE) results from excessive production of bradykinin, a potent vasodilatory mediator. Bradykinin also has important vascular permeability-enhancing effects. During episodes of angioedema in patients with HAE, plasma bradykinin levels have been shown to be sevenfold higher than normal . In bradykinin-mediated angioedema, histamine and other mast cell mediators are not directly involved, which explains the lack of response to antihistamines and distinguishes this form of angioedema from the histamine-mediated angioedema that is seen in allergic reactions and urticaria.
Some forms of HAE arise from deficiency or dysfunction of C1 inhibitor (C1INH), while others do not. In those that do not, specific mutations in the factor XII gene have been identified in some families, while the etiopathogenesis of the disease in other families is unknown.
Functions of C1 inhibitor — C1 inhibitor (C1INH) is an acute-phase reactant and a member of the "serpin" superfamily of serine protease inhibitors. C1INH is an inhibitor of two complement pathways (classical and lectin), as well as of the intrinsic coagulation (contact system) fibrinolytic  and kinin-generating pathways. Within these different pathways, C1INH inhibits several plasma proteases: C1r and C1s, mannose-binding lectin-associated serine proteases (MASP1 and MASP2), coagulation factor XII (Hageman factor), coagulation factor XI, plasma kallikrein, and plasmin [3-6]. The function of C1INH in the kinin-generating pathway is most directly related to the pathogenesis of HAE (figure 1) [7-9].To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
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- Functions of C1 inhibitor
- Molecular events leading to angioedema
- Subtypes and genetics
- - Hereditary angioedema with C1 inhibitor deficiency/dysfunction
- Inheritance patterns
- - Hereditary angioedema with normal C1 inhibitor
- When to suspect hereditary angioedema
- Trial of high-dose antihistamines
- Complement testing
- Algorithmic approach to evaluation
- - Low clinical suspicion
- - High clinical suspicion
- Interpretation of complement tests
- TESTING FAMILY MEMBERS
- Accuracy of testing in infants
- DIFFERENTIAL DIAGNOSIS
- Cutaneous and/or laryngeal swelling
- Low C4 levels
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- SUMMARY AND RECOMMENDATIONS