**3. Pathogenesis**

defined as non‐functioning C1‐inh. These diseases are called type I and type II HAE, respec‐ tively [3, 4]. These laboratory abnormalities in C1‐inh are the result of the mutations found in the C1‐inh gene called SERPING1 [5]. In the 2000s, a third form of HAE was defined and in these patients characteristic clinical signs and symptoms are seen; however, the level and the function of C1‐inh are normal with no mutations on the SERPING1 gene [6, 7]. However, mutations in the F12 gene were found in approximately 25% of these patients. A strong asso‐ ciation between this type of HAE and conditions causing increased levels of estrogen such as pregnancy and the usage of oral contraceptives was determined [7, 8]. Therefore, at first, this type was called estrogen‐dependent or type III hereditary angioedema [6]. After affected male relatives were reported, it was renamed as hereditary angioedema with normal C1‐inh [9].

HAE is rarely seen, and its estimated prevalence ranges from 1:30,000 to 1:80,000 in the gen‐ eral population [10]. The most common form of HAE is the first type, which is responsible for 85% of the patients [10]. HAE is an autosomal dominant disease generally affecting all generations in a family, although a quarter of patients do not have a family history. Patients are similarly affected independent of gender and ethnicity [11]. Mortality rates range from 14 to 33% mostly because of poorly treated laryngeal episodes, which indicates the significance

Symptoms primarily develop when the serum level of C1‐inh is below 35% but are not usually correlated with serum C1‐inh levels. Symptoms can be expected from birth in a heterozygote individual with a serum level of C1‐inh around 50% [14]. Although signs and symptoms can start at any age, including after 70, they are primarily seen starting around the second decade of life when the level of C1‐inh usually decreases and then continues to occur lifelong [14, 15]. Angioedema episodes can affect any cutaneous or mucosal sites of the body such as the face, larynx, extremities, gastrointestinal tract, and urogenital area [1]. A typical HAE episode worsens within the first 24 h, begins to improve after 48–72 h, and lasts approximately 72–96 h [11, 14]. Apart from visible angioedema, fluid extravasation on the gastrointestinal tractus through the intestinal wall or peritoneum leads to abdominal pain attacks. Nausea and emesis may accompany them [16]. The majority of the patients experience gastrointestinal angio‐ edema during their lives and the abdominal attacks accompany 50% of the overall attacks [17]. Due to these abdominal attacks, unnecessary operations like appendectomy and diagnostic laparotomy are sometimes performed [16]. Fever or leucocytosis is not observed during a typi‐ cal attack unless the cause is an infection [18]. Sometimes, fluid extravasation can be so severe that it causes hypotension or ascites [19]. The most severe complication is angioedema in the larynx and/or oropharynx, which can prevent air passage leading to asphyxiation or even death. Fortunately, this seems less frequent [16]. More than 50% of the patients experience

Although the precipitating factors of attacks are not well determined in all attacks, some episodes of HAE can be triggered by factors such as stress, trauma, infection, angiotensin‐ converting enzyme inhibitors (ACEIs), estrogen‐containing hormones, oropharyngeal surgery,

of early diagnosis and appropriate management [12, 13].

laryngeal edema at least once in their lifetime [20].

**2. Clinical presentation**

134 A Comprehensive Review of Urticaria and Angioedema

C1‐inh is a broad‐spectrum serine proteinase inhibitor, which regulates the activity of various proteases comprising those of the contact system, the intrinsic coagulation pathway, and the fibrinolytic pathway [5]. C1‐inh is produced primarily in the liver and inhibits the plasma kal‐ likrein, a type of protease that cleaves high‐molecular‐weight kininogen (HMWK) to produce bradykinin and also inhibits activated coagulation factor XII (FXII), which in turn enhances the activation of the contact system by activating the plasma kallikrein [10].

Trauma as well as surgical interventions causing a negatively charged endothelial surface and a deficiency in the serum level of C1‐inh leads to the development of FXIIa in significant amounts. FXIIa induces the transformation of prekallikrein to kallikrein, which in turn leads to the cleavage of high‐molecular‐weight kininogen to bradykinin [10, 14] (**Figure 1**).

The major mediator responsible for angioedema is a type of nanopeptide called bradykinin. Bradykinin is formed secondary to the activation of the contact system. It leads to an increase in vascular permeability by binding to the B2 receptor on the vascular endothelial cells, and this in turn causes the development of edema, ascites, and hypotension [25, 26].

C1‐inh is encoded by the SERPING1 gene which is located on the 11th chromosome. Around 300 different mutations of the SERPING1 gene were identified in both type I and type II HAE patients. Approximately a quarter of patients with C1‐inh deficiency do not have a family his‐ tory, indicating the occurrence of de novo mutations. In type I HAE, various types of muta‐ tions involving nonsense, missense, insertion, or deletion mutations developed throughout SERPING1 leading to a decrease in the serum level of C1‐inh [10, 27]. By contrast, almost all

**Figure 1.** The role of C1‐inh in the plasma cascade and complement pathway and the pathogenesis of the HAE [14]. (With permission from Massachusetts Medical Society).

of the mutations in type II HAE are missense at or near the active site causing the production of a defective protein, which cannot act properly [10]. In patients with HAE with normal C1‐inh, the SERPING1 gene is not mutated, but in some of these patients mutations on the FXII gene, which is located on the fifth chromosome, can be detected. The pathomechanism of angioedema in these patients is not well defined. One of the detected mutations on factor XII leads to a gain of function, which is thought to cause the increase in the production of bradykinin [28]. However, this hypothesis was not confirmed in another study [29]. Since bradykinin antagonist drugs are effective in uncontrolled patients, it can be assumed that this type of angioedema is also bradykinin mediated [10].
