Distinct Conditions Support a Novel Classification for Bradykinin-Mediated Angio-Oedema

Abstract

Background: Angio-oedema (AO) can be attributable to bradykinin (BK) accumulation, as is the case for prototypical hereditary AO (HAO) due to C1 inhibitor (C1-INH) deficiency. However, our clinical experience in a reference centre has shown that some patients display a clinical history suggestive of HAO, but exhibit normal C1-INH function, have no mutation in the causative genes associated with HAO (SERPING1, F12), and report no intake of drugs known to promote AO. Objective: We sought to determine the frequency and distribution of different AO subtypes suspected to be BK-mediated AO (BK-AO) and defined by clinical, history and biological criteria (enzyme activities implicated in BK formation and catabolism). Methods: The files of all patients referred to our centre for suspected BK-AO were retrospectively analysed. Results: The distribution of patients (n = 162) was 16 and 4% with a hereditary deficiency of C1-INH or a gain of factor XII function, respectively, 29% with iatrogenic BK-AO, 21% with non-iatrogenic defective kininase activity and 30% with idiopathic increased kinin formation. Conclusion: BK-AO may be caused by multiple inherited or acquired factors triggering BK accumulation. Therefore, we propose a novel typology for BK-AO based on the imbalance of production/catabolism of BK.

Urticaria and Prodromal Symptoms Including Erythema Marginatum in Danish Patients with Hereditary Angioedema

“…However, bradykinin-mediated angioedema should not be ruled out solely on the presence of a positive medical history for urticarial lesions (22). Recently interesting studies on murine C1INH knock-out models have revealed a possible role of subclinical mast cell activation in the initiation of attacks in patients with HAE.…”

Kininogen Cleavage Assay: Diagnostic Assistance for Kinin-Mediated Angioedema Conditions

“…Angioedema manifests as self-limiting oedema affecting the subcutaneous and sub-mucosal tissues. It is most commonly associated with wheals in conjunction with urticaria, an histamine mediated-, mast cell degranulation related disease [ 1 , 2 ]. Angioedema without wheals (AE) is considered an independent symptom [ 1 ], and has been defined as nonpruritic, nonpitting, and resistant to H1 antihistamine drugs [ 3 , 4 ].…”

“…AE can prove life-threatening if the upper airways are affected, though symptom intensity and frequency vary widely, even within the same family [ 3 , 4 ]. AE is usually divided according to its hereditary or acquired origin [ 1 ], but other classifications have been proposed [ 2 , 5 ] and we will use the level of functional C1Inhibitor (C1Inh) as the main classification factor.…”

“…The nC1Inh-AE can also occur without FXII mutation, triggered by oral oestrogen/progestin combination (OP) intake [ 15 – 17 ] through possible transcriptional regulations which remain to be formally explicated [ 5 ]. Since BK is degraded by several peptidases, including angiotensin-converting enzyme (ACE), ACE inhibitor treatment can trigger AE (ACEi-AE, OMIM 300909) [ 1 , 5 , 18 ] but other BK degrading peptidases might also be implicated [ 2 , 18 ]. Finally there are idiopathic or even allergic AE (I-AE), where the relative involvement of BK and histamine pathways is unclear and noticed mainly by response to treatment [ 1 , 5 , 19 ].…”

Pediatric hereditary angioedema: an update

“…C1-Inh-HAE represents one in five patients presenting with kinin-dependent angioedema, the great majority associated with heredity, and identified as nC1-Inh-HAE 50 . C1-Inh-HAE could be considered as a prototypical condition for extending clinical trials to patient groups identified by ongoing and foreseen biomarkers and susceptibility genes.…”