**7. Classification of angioedema due to functionally active C1 esterase inhibitor protein (C1 inhibitor) deficiency**

Functionally active C1‐INH deficiency can be hereditary or acquired. The hereditary form is a primary immunodeficiency [25] and is the most common genetic defect of the complement system [26]. The absence or malfunction of C1‐INH results in the presence of attacks of AE (subcutaneous or mucosal swelling) due to uncontrolled activation of the contact system, with the generation of bradykinin, a vasoactive peptide released from HMWK [9].

#### **7.1. Hereditary angioedema**

C1‐INH‐HAE is a genetic autosomal dominant disease characterized by a deficiency of the functionally active C1 esterase inhibitor (C1 inhibitor) protein. Initially, it was believed that it affected one individual per 10,000–150,000 people, but being a rare disease it makes an estimate of prevalence difficult to pinpoint [27]. It could affect around 2000–3000 people in the USA [28]. There is a register of patients in Spain where the minimum prevalence is 1.09 per 100,000 inhabitants [29], while another register in Denmark describes a prevalence rate of 1.41 per 100,000 inhabitants [30]. The highest published prevalence is in Norway with 1.75 per 100,000 inhabitants [31]. Delays in diagnosis (an average of 13.1 years in the Spanish study) [29] along with the possibility of misdiagnosis and lack of recognition of the disease may mean that the true prevalence may be higher than estimates suggest. To date, no studies have shown differences in prevalence between ethnic groups.

Two phenotypic variants were described [32, 33]*. Type I* (HAE‐I) is the most common (85%), characterized by a quantitative decrease of C1‐INH, which results in a decrease in functional activity; *type II* (HAE‐II) (15%) is characterized by normal or elevated levels of dysfunctional C1‐INH. In both cases, the defect is transmitted as an autosomal dominant form, although with different genetic alterations. There is another estrogen‐dependent hereditary AE variant in which both levels and function of C1‐INH are normal and which has been called HAE *type III* [34, 35].

#### **7.2. Acquired angioedema**

C1‐INH‐AAE is biochemically characterized by low C1‐INH concentrations and/or functions and no evidence of heredity. It is mainly associated with B cell lymphoproliferative disorders and occasionally with autoimmune, neoplastic, or infectious diseases [14]. Initially, it was classified into two types: type I, with most patients having an associated B cell line malignancy; type II, there were anti‐C1‐INH autoantibodies that interfered with C1‐INH functional activity [36]. C1‐INH production is normal or slightly increased. In many patients with type I, the paraproteinemia or M component actually behaves as an anti‐C1‐INH autoantibody, so some authors such as Cicardi suggest that the distinction between types I and II may be artificial [37].

Acquired C1‐INH deficiency is characterized by the activation of the classical complement pathway and accelerated catabolism of C1‐INH and the activation of the contact system [9]. This results in low C4 and C2 levels and normal C3 levels in plasma. C1q levels are frequently very low in C1‐INH‐AAE and this feature is frequently used to differentiate the acquired from the hereditary form of C1‐INH deficiency [14].
