An Update on the Diagnosis and Management of Hereditary Angioedema With Abnormal C1 Inhibitor

Hereditary angioedema (HAE) is a rare genetic disease caused by a deficiency in functional C1-esterase inhibitor (C1 INH) characterized by recurrent episodes of nonpruritic, subcutaneous, or submucosal edema commonly involving the bowels, genitalia, trunk, extremities, face, tongue, or larynx.^1,2 The estimated frequency of HAE is 1 in 50,000 individuals in the general population without differences in race or sex.¹ There are 2 primary types of HAE associated with abnormal levels of C1 INH. Type I, characterized by decreased levels of C1 INH antigen in the plasma, accounts for approximately 85% of cases. Type II is characterized by the expression of a dysfunctional C1 INH protein with normal or slightly elevated levels of C1 INH antigen, and accounts for approximately 15% of cases.^2,3 Distinctly, a third type of HAE, deemed HAE with normal C1 INH, has been described in patients who express normal functioning C1 INH but suffer the classic recurrent attacks of angioedema.⁴ Although in the United States, most HAE patient’s care is managed by allergists and clinical immunologists, most urticaria and angioedema may be seen first by dermatologists, requiring a clear understanding of HAE and its therapeutic management. In contrast, the majority of European patients are under the care of dermatologists and hematologists. This review will focus on the diagnosis and management of patients with HAE with CI INH deficiency.

C1 INH is a serine protease inhibitor that inhibits several complement proteases including C1r, C1s, and mannan-binding lectin-associated proteases (MASPs) 1 and 2. C1 INH also inactivates plasma kallikrein, and coagulation factors XIa and XIIa, thereby regulating activation of the contact system and the intrinsic coagulation pathway.³ Regulation of these systems is performed through the formation of complexes between the proteases and the inhibitor, resulting in inactivation of both and consumption of the C1 INH. HAE patients already have low levels of endogenous or functional C1 INH and further consumption may trigger an attack. Without enough C1 INH to regulate the contact system, the activation of kallikrein goes unchecked and cleaves high-molecular-weight kininogen, which frees the potent mediator responsible for the vascular permeability, bradykinin (Figure 1).

Angioedematous episodes usually begin in patients between the ages of 5 and 11 years, with the majority of the first episodes beginning by age 20, but they may occur at any age⁵ (Figure 2). HAE should be suspected in patients with recurrent angioedema or abdominal pain in the absence of associated urticaria. HAE attacks are commonly preceded by a prodrome, usually a tingling sensation.² In addition, erythema marginatum, a nonpruritic, serpiginous rash, accompanies about one third of HAE attacks. Subcutaneous swellings are the most common angioedematous episodes (Figure 3). Abdominal swellings affecting the submucosa of the bowel, which are associated with severe pain, nausea, and vomiting, are also frequently seen and can be very incapacitating. A laryngeal