Hereditary and Acquired Angioedema: Heterogeneity of Pathogenesis and Clinical Phenotypes

Abstract

Recurrent angioedema (AE) without wheals is increasingly recognized as a clinical entity and a frequent cause of admission to the emergency room. The Hereditary Angioedema Working Group (HAWK) classification allowed the scientific community to go beyond the semantic confusion that dominated this topic for decades. This classification distinguishes hereditary and acquired forms of AE, either related or unrelated to C1 inhibitor deficiency. Recently, additional mechanisms have been involved in the AE pathogenesis, including the uncontrolled activation of factor XII, generation of vasoactive mediators that induce dysregulation of endothelial functions, and bidirectional interactions between mast cell-derived mediators and the plasma contact system. Thus, recurrent AE can be determined by multiple and concurrent mechanisms that may generate distinct clinical phenotypes of the disease. Frequency, severity, and the location of attacks are quite different from patient to patient and, even in the same patient, they may change throughout the course of life. The severity of the clinical phenotype strongly influences the burden of the disease and patients’ quality of life. Despite major advances in our understanding of recurrent AE, many unsolved questions remain, leaving several unmet needs for patients and caregivers. This review is focused on a description of different AE phenotypes and the concurrent mechanisms leading to their pathogenesis. A better definition of cellular and molecular pathways responsible for the distinct AE phenotypes may help to improve diagnosis and may lead to a personalized approach to prophylaxis and treatment of the disease.

Patterns of C1-Inhibitor/Plasma Serine Protease Complexes in Healthy Humans and in Hereditary Angioedema Patients

“…It can inhibit a number of target proteases and, due to its multi-functional role, C1-INH is the key regulator of the complement and contact systems, and is also involved in the control of blood coagulation and fibrinolysis (2). Hereditary or acquired deficiency of C1-INH leads to the occurrence of angioedematous symptoms, affecting subcutaneous or the submucosal tissues (3,4). Recognizing C1-INH deficiency is indispensable, because, without appropriate treatment, angioedema may severely impair quality of life or even cause death (5).…”

Phenocopies: Mimics of Inborn Errors of Immunity

“…The presence of this autoantibodies is related with the duration of disease activity [91]. Table 4 shows the useful clinical data for an adequate differential diagnosis in patients with angioedema and in whom this phenocopy is suspected [92].…”

Recent Advances in Clinical Allergy and Immunology

“…Recent research has provided evidence that there is a heterogeneity of pathogenesis and phenotypes that allows a classification of subgroups, the establishment of diagnostic algorithms, and also has implications for treatment [72]. The characterization of patients with recurrent AE without urticaria reveals distinct subgroups based on clinical data and complement screening [73].…”