Hereditary angioedema

Journal of Drugs in Dermatology, Oct, 2006 by Michael M. Sachse, Amor Khachemoune, Kjetil K. Guldbakke, Michael Kirschfink

Abstract

Hereditary angioedema (HAE) is a rare autosomal dominant disorder caused by a CI-inhibitor deficiency. It is characterized by potentially life-threatening recurrent episodes of angioedema of the skin and mucosa. Several recent studies have further elucidated the immunology of HAE implicating bradykinin, the key mediator of the contact system. This article reviews the pathophysiology, subtypes, and clinical features of HAE. Therapeutic approaches for various clinical situations (emergency and prophylactic regimens) are also discussed.

Introduction

Hereditary angioedema (HAE) was first described by Milton in 1876. (1) Six years later, Quincke introduced the term angioneurotic edema, suggesting a possible link between mental stress (such as emotional stress, trauma, surgery, or menses) and exacerbation of the disease. (2,3) It took more than 80 years before the C1 esterase inhibitor (C1-INH) deficiency was identified as the main cause of HAE. (4)

The worldwide incidence rates of HAE vary between 1:10,000 and 1:150,000. Approximately 40% of patients have their first onset before the age of 5, and 75% present before the age of 15. (5) Up to 40% of all undiagnosed patients with HAE die as a result of upper airways obstruction. The development of new therapeutic options is showing great promise in reducing the incidence of life-threatening attacks. (6) Even so, there is still a need to further elucidate the pathophysiology, as well as to improve its treatment and prophylaxis. (7)

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Pathophysiology

C1-INH deficiency was identified as the main cause of HAE. In contrast to urticaria, where the edema involves the papillary and mid-dermis, angioedema affects both the reticular dermis and the subcutaneous and/or submucosal tissue. (8,9) The main biological role of the C1-INH protein lies in its regulatory function of the complement as well as the contact systems (Figure 1). Normal levels of C1-INH prevent the spontaneous activation of C1; representing the first step in the classic complement pathway. C1-INH exerts a similar regulatory function in the lectin pathways. (10) Complement is activated via the classical, the alternative, or the lectin pathway. (11,12) Once initiated, this cascade leads to the generation of the vasoactive anaphylatoxins C3a, C4a, and C5a, as well as the assembly of the membrane attack complex. (13)

Under physiologic conditions, C1-INH inactivates and thereby regulates about 90% of activated factor XII (XIIa), including its metabolite co-factor XIIf. In the contact (kallikrein-kinin) system, factor XII is activated upon contact with negatively charged tissue and endothelial surfaces (ie, during surgery), leading to the formation of kallikrein and bradykinin. Recent data suggest that bradykinin is the main mediator resulting in vasodilatation, nonvascular smooth muscle contraction, and edema formation, thus resulting in the acute symptoms of HAE.

In patients with HAE, a C1-INH deficiency results in dysregulation of both the complement and the contact systems resulting in edema that affects both the reticular dermis and the subcutaneous and/or submucosal tissue. (7-9)

Genetics, Prevalence, and Types

There are 2 classical types of HAE, both caused by an inherited autosomal dominant defect of the C1-INH gene mapped to chromosome 11 (11q12-q13.1). (9) No sex or race predominance has been identified. More than 100 different mutations have been described so far, with a spontaneous mutation rate of up to 25%. (14) The 2 subtypes can be subdivided based on plasma levels and functional activity of C1-INH. Up to 85% of patients belong to HAE type 1, in which the amount of the active regulator is decreased. In contrast, HAE type 2 is characterized by normal or even elevated C1-INH levels; however, the C1-INH in this type lacks its full functional activity. (7) More recently, Bork et al described HAE type 3, which almost exclusively affects women. In this type, patients present with a typical clinical picture, but have a normal C1-INH concentration and function. (15)

Clinical Features

Most patients with HAE have a personal or family background of mild recurrent attacks of angioedema or abdominal pain. An important exception to this are patients with a spontaneous mutation. (5) Angioedema has been found to be triggered by various surgical procedures, pregnancy, mental stress, and drugs such as estrogen and angiotensin-converting enzyme (ACE) inhibitors. The combined administration of ACE inhibitors and estrogens is contraindicated. (5,9,16,17) More recently, an exacerbation of HAE type III due to angiotensin II receptor antagonists was postulated. (18) HAE may also be associated with several autoimmune diseases including glomerulonephritis, Sjogren's syndrome, thyroiditis, and lupus erythematosus, as well as some coagulopathies. (9)

Cutaneous angioedema of an extremity is the first presenting sign in 75% of patients. The edema tends to be recurrent, non-pitting, and non-pruritic, mainly affecting the extremities, the genitalia, and the face. A prodromal erythema has been described in up to 25% of patients. (19) Twenty-five percent of patients also suffer from gastrointestinal symptoms such as abdominal cramps and nausea. (20) Attacks of angioedema tend to develop gradually over 12 to 36 hours. Of note, there are reports of upper airway affection within 5 to 20 minutes of the onset. (21,22) While cutaneous signs may last up to 5 days, gastrointestinal symptoms usually subside within 24 hours. (5,7,23)