Angioedema is a prevailing symptom in different diseases, frequently occurring in
the presence of urticaria. Recurrent angioedema without urticaria (AE) can be hereditary
(HAE) and acquired (AAE), and several subtypes can be distinguished, although clinical
presentation is quite similar in some of them. They present with subcutaneous and
mucosal swellings, affecting extremities, face, genitals, bowels, and upper airways.
AE is commonly misdiagnosed due to restricted access and availability of appropriate
laboratorial tests. HAE with C1 inhibitor defect is associated with quantitative and/or
functional deficiency. Although bradykinin-mediated disease results mainly from disturbance
in the kallikrein-kinin system, traditionally complement evaluation has been used
for diagnosis. Diagnosis is established by nephelometry, turbidimetry, or radial immunodiffusion
for quantitative measurement of C1 inhibitor, and chromogenic assay or ELISA has been
used for functional C1-INH analysis. Wrong handling of the samples can lead to misdiagnosis
and, consequently, mistaken inappropriate approaches. Dried blood spot (DBS) tests
have been used for decades in newborn screening for certain metabolic diseases, and
there has been growing interest in their use for other congenital conditions. Recently,
DBS is now proposed as an efficient tool to diagnose HAE with C1 inhibitor deficiency,
and its use would improve the access to outbound areas and family members. Regarding
HAE with normal C1 inhibitor, complement assays' results are normal and the genetic
sequencing of target genes, such as exon 9 of F12 and PLG, is the only available method.
New methods to measure cleaved high-molecular-weight kininogen and activated plasma
kallikrein have emerged as potential biochemical tests to identify bradykinin-mediated
angioedema. Validated biomarkers of kallikrein-kinin system activation could be helpful
in differentiating mechanisms of angioedema. Our aim is to focus on the capability
to differentiate histaminergic AE from bradykinin-mediated AE. In addition, we will
describe the challenges developing specific tests like direct bradykinin measurements.
The need for quality tests to improve the diagnosis is well represented by the variability
of results in functional assays.
