Abstract
BackgroundThe kinins (primarily bradykinin, BK) represent the mediators responsible for local increase of vascular permeability in hereditary angioedema (HAE), HAE I-II associated with alterations of the SERPING1 gene and HAE with normal C1-Inhibitor function (HAE-nC1INH). Besides C1-Inhibitor function and concentration, no biological assay of kinin metabolism is actually available to help physicians for the diagnosis of angioedema (AE). We describe enzymatic tests on the plasma for diagnosis of BK-dependent AE.MethodsThe plasma amidase assays are performed using the Pro-Phe-Arg-p-nitroanilide peptide substrate to evaluate the spontaneous amidase activity and the proenzyme activation. We analyzed data of 872 patients presenting with BK-dependent AE or BK-unrelated diseases, compared to 303 controls. Anti-high MW kininogen (HK) immunoblot was achieved to confirm HK cleavage in exemplary samples. Reproducibility, repeatability, limit of blank, limit of detection, precision, linearity and receiver operating characteristics (ROC) were used to calculate the diagnostic performance of the assays.ResultsSpontaneous amidase activity was significantly increased in all BK-dependent AE, associated with the acute phase of disease in HAE-nC1INH, but preserved in BK-unrelated disorders. The increase of the amidase activity was associated to HK proteolysis, indicating its relevance to identify kininogenase activity. The oestrogens, known for precipitating AE episodes, were found as triggers of enzymatic activity. Calculations from ROC curves gave the optimum diagnostic cut-off for women (9.3 nmol⋅min−1⋅mL−1, area under curve [AUC] 92.1%, sensitivity 80.0%, and specificity 90.1%) and for men (6.6 nmol·min−1⋅mL−1, AUC 91.0%, sensitivity 87.0% and specificity 81.2%).ConclusionThe amidase assay represents a diagnostic tool to help physicians in the decision to distinguish between BK-related and –unrelated AE.
Highlights
Kinin-mediated angioedema (AE) is an uncommon disorder characterized by recurrent and unpredictable episodes of localized swelling, due to increased vascular permeability in subcutaneous and submucosal tissues [1,2]
Patients We collected citrate plasma samples from patients diagnosed with hereditary angioedema (HAE) I-II (n = 250; 217 HAE I, 33 HAE II; 95 males/155 females), with AAE (n = 20; 8 males/12 females), and with HAE
A large group of the women (64/239, 27%) suffering from HAE-nC1INH reported worsening of symptoms during oestrogen contraceptive (OC) therapy (n = 57) and/or pregnancy (n = 7)
Summary
Kinin-mediated angioedema (AE) is an uncommon disorder characterized by recurrent and unpredictable episodes of localized swelling (face, extremities, bowel wall, genitals and upper airways), due to increased vascular permeability in subcutaneous and submucosal tissues [1,2]. HAE I–II and AAE diagnoses are based on the clinical picture in combination with a laboratory diagnosis demonstrating reduced C1INH function (,50%) associated or not with low levels of C1INH and C4 [9]. We [10] and others [11,12] have described HAE with normal C1INH function (HAEnC1INH) manifesting as recurrent AE with possible association with F12 gene mutations [13,14]. When the F12 gene is normal, the absence of biological diagnosis is a true limit for the clinical practice and management of a majority of patients suffering from presumable HAE-nC1INH. The kinins (primarily bradykinin, BK) represent the mediators responsible for local increase of vascular permeability in hereditary angioedema (HAE), HAE I-II associated with alterations of the SERPING1 gene and HAE with normal C1-Inhibitor function (HAE-nC1INH). We describe enzymatic tests on the plasma for diagnosis of BK-dependent AE
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