Hereditary Angioedema Type 2

The clinical presentation is identical to HAE type 1. Angioedema, defined as sudden onset of edema involving the subcutaneous tissues of the extremities and face, but also the respiratory and gastrointestinal tract, is the main feature of HAE type 2. GI edema manifests as severe abdominal pain and cramping (mimicking acute abdomen), while laryngeal edema may cause breathing difficulties and even asphyxiation [3]. An erythematous, nonpruritic, nonpitting rash known as erythema marginatum is frequently noted in HAE patients and should be easily distinguished from urticaria. Symptoms usually resolve in 12-72 hours, but their frequent occurrence often mandates adequate therapy.

A properly obtained patient history including the frequency of attacks and data regarding the familial presence of symptoms may be the key in making an initial diagnosis. Laboratory studies are necessary to confirm HAE, however, and serum levels of C1-INH and its function, as well as C4 (which is consumed during acute attacks), should be evaluated [2]. Patients in whom functional activity of C1-INH is reduced, but with normal serum concentration, are diagnostic of HAE type 2.

HAE attacks do not respond to corticosteroids, antihistamines, or adrenaline and the use of other agents is necessary. Icatibant (a competitive bradykinin receptor antagonist), ecallantide (inhibitor of kallikrein) and either recombinant or human C1-INH are drugs of choice for relieving acute symptoms [1]. On the other hand, attenuated androgens are used for long-term prophylaxis, with danazol, stanozolol, and oxandrolone being most frequently used [4] [5]. It must be emphasized, however, that androgens are strongly contraindicated in pregnant women due to their teratogenic effects, particularly in the first trimester [4]. Patients (especially pregnant women) should be trained for self-administration of therapy at home, the primary reason being the associated morbidity and mortality from delayed treatment [4].

Management of symptoms with proper therapy is very good, but approximately 50% of patients develop at least one episode of laryngeal edema, which may be life-threatening in some cases [1]. Other studies have shown that untreated HAE can cause at least 1 acute attack per month and individuals may experience a severe reduction in their quality of life for 20-100 days on an annual basis [2]. For this reason, an early diagnosis is detrimental.

HAE type II stems from impaired function of a normally synthesized C1-INH, the primary reason being mutations in genes that code for this protein [3]. Point mutations, most frequently missense, of SERPING1 genes located on chromosome 11, are responsible for production of a dysfunctional C1-INH [3].

An estimated global prevalence of HAE ranges between 1:10,000 and 1:50,000, with 15% of cases attributed to type 2 [1]. Several provoking factors of HAE have been described, including trauma, emotional stress (eg. weddings, Christmas, etc.), use of oral contraceptives and angiotensin-converting-enzyme inhibitor (ACE inhibitor), as well as infections [1]. A predilection of HAE type 2 toward female gender was observed in some studies, with the most probable reason being a strong association between the onset of symptoms and estrogen, but the exact connection remains to be elucidated [4].

Under physiological conditions, C1-INH inhibits the production of kallikrein and factor XII-mediated complement stimulation [2]. In the setting of its improper activity, abnormal production of kallikrein, and bradykinin as the end-product leads to a profound onset of edema due to markedly increased vascular permeability in tissues [2] [3]. It must be emphasized that histamine is not the principal mediator of symptoms in HAE of all types, which is why the presence of urticaria (hives) can immediately exclude HAE from the differential diagnosis [3].

Fortunately, drugs that are used for management of acute attacks may also be used as prophylaxis. Plasma-derived C1-INH is given 1-6 hours prior to surgical or dental procedures as a preventive measure, whereas long-term use of androgens has shown very good results in reducing the number of acute exacerbations down to a minimum [4].

Hereditary angioedema (HAE) is a rare genetic disease divided into three types and type 2, encompassing approximately 15% of all HAE cases, is characterized by a poor functional activity of C1-esterase inhibitor (C1-INH) [1] [2]. Mutations in the C1-INH protein, coded by C1-INH genes on chromosome 11, is the underlying cause and approximately 20-25% of mutations arise de novo [2]. The remaining patients, however, inherit these mutations through an autosomal dominant pattern, suggesting a strong familial component in HAE [2]. Symptoms stem from excessive generation of bradykinin due to the inability of dysfunctional C1-INH to suppress its production and include an abrupt onset of erythema marginatum (non-pruritic and non-pitting rash), edema on the extremities and face and severe abdominal pain [3]. The clinical presentation is indistinguishable from hereditary angioedema type 1 (caused by a deficiency of C1-INH), which is why laboratory tests to determine the levels of C1-INH should be performed. Bradykinin receptor antagonists (icatibant), recombinant or human C1-INH, antifibrinolytics (tranexamic acid), and kallikrein inhibitors (ecallantide) are recommended for treatment of acute attacks [1] [4], while attenuated androgens - danazol, stanozolol, or oxandrolone are used for long-term prophylaxis [1] [5]. Androgens are contraindicated in pregnancy, however, as they can cross the placenta and exert teratogenic effects [4].

Hereditary angioedema (HAE) is a rare genetic disorder demarcated by an acute and abrupt onset of edema of the face and extremities, severe abdominal pain and a rash (known as erythema marginatum) due to mutations of an enzyme responsible for various functions in the immune system. There are three distinct types and in type 2, production of this enzyme (C1-esterase inhibitor, or C1-INH) is normal, but the synthesized protein is dysfunctional and is unable to perform its function. As a result, typical symptoms appear and are often related to triggering events such as infections, pregnancy (in which more frequent attacks are observed), use of oral contraceptives and ACE inhibitors, but also emotional stress. The diagnosis is made after conducting blood tests to assess the levels of C1-INH and its functional activity. Management of acute attacks and long-term use of drugs to prevent their occurrence is the mainstay of treatment and patients should be trained for self-treatment at home, in order to prevent life-threatening edema of the larynx that can cause cessation of breathing if treatment is delayed. HAE can be a debilitating disease in the absence of appropriate therapy, which is why an early diagnosis carries a very good prognosis and minimal impairment of daily life.

1. Kargarsharif F, Mehranmehr N, Zahedi Fard S, Fazlollahi MR, Ayazi M, Mohammadzadeh I, et al. Type I and Type II Hereditary Angioedema: Clinical and Laboratory Findings in Iranian Patients. Arch Iran Med. 2015;18(7):425-429.
2. Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Intern Med. 2001;161(20):2417-2429.
3. Cichon S, Martin L, Hennies HC, et al. Increased Activity of Coagulation Factor XII (Hageman Factor) Causes Hereditary Angioedema Type III. Am J Hum Genet. 2006;79(6):1098-1104.
4. Caballero T, Canabal J, Rivero-Paparoni D, Cabañas R. Management of hereditary angioedema in pregnant women: a review. Int J Womens Health. 2014;6:839-848.
5. Floccard B, Hautin E, Bouillet L, Coppere B, Allaouchiche B. An evidence-based review of the potential role of icatibant in the treatment of acute attacks in hereditary angioedema type I and II. Core Evid. 2012;7:105–114.