Potential Blood Biomarkers for Types of Angioedema Noted in Study
Higher blood levels of molecules involved in blood vessel formation and permeability — Tie-2, Ang-2, and VE-Cadherin — along with sE-selectin, which is involved in vascular inflammation, may help to distinguish different types of angioedema, a study suggests.
Notably, Tie-2 may be a biomarker of hereditary angioedema (HAE), while Ang-2 may mark bradykinin-mediated angioedema, including HAE and angiotensin-converting enzyme (ACE)-inhibitor-induced angioedema (ACE-AE).
Future studies are needed to confirm these findings, and the value of using these molecules as biomarkers of angioedema’s main types, the researchers noted.
The study, “Identification of novel biomarkers to distinguish bradykinin-mediated angioedema from mast cell-/histamine-mediated angioedema,” was published in the journal Allergy.
Angioedema is characterized by swelling in the deep layers of the skin or mucous membranes, most commonly caused by small blood vessels becoming more permeable, or leaky.
The disease can be divided into three main groups according to the initiating mediator: bradykinin-mediated angioedema (BK-AE), histamine- or mast cell-mediated angioedema (acute allergic angioedema), and angioedema of unknown cause (idiopathic angioedema).
Acute allergic angioedema is caused by allergic reactions, while BK-AE is associated with higher-than-normal levels of bradykinin — an inflammatory molecule that leads to sudden swelling and pain attacks. BK-AE includes HAE, which is caused by certain genetic mutations, and ACE-AE, which is associated with the use of ACE inhibitors to treat high blood pressure.
“Identification of the respective angioedema type is challenging and crucial for choosing the adequate therapy,” the researchers wrote, adding that there is “a lack of reliable markers” to differentiate one type from another.
Scientists in Germany set out to identify clinical and laboratory parameters specific for certain angioedema types by analyzing data from 15 people with HAE, 13 ACE-AE patients, 12 people with mast cell-/histamine-mediated angioedema without wheals in chronic spontaneous urticaria (CSU-AE), and 10 healthy individuals.
Patients’ mean age was 41.4 years for the HAE group, 48 for the CSU-AE group, and 60.7 for the ACE-AE group.
Results showed that no new clinical diagnostic criteria could be identified. But psychological stress, a known trigger of angioedema attacks in HAE and CSU-AE, was also the most commonly reported trigger in the ACE-AE group, in which triggering factors “are far from being clear,” the researchers wrote.
Early, or prodromal, symptoms of swelling attacks were reported by 46.7% of HAE patients, consistent with previous findings, and by 53.8% of ACE-AE patients — a patient population in which these early signs have not been extensively reported.
HAE patients also showed significantly lower counts of monocytes relative to those with CSU-AE. Monocytes are a type of immune cell that, along with the liver, are the main producers of a protein called C1-esterase inhibitor (C1-INH), whose activity is deficient in HAE.
“Despite the finding that some clinical characteristics were more frequently associated with a certain angioedema type, there was no diagnostic clue,” the researchers wrote. Future research should address these interesting clinical findings, such as “prodromal symptoms and the role of psychological stress in ACE-AE and absolute monocyte counts in HAE.”
Regarding laboratory findings, the blood levels of certain molecules related to blood vessel formation and permeability, or leaking — Tie-2, Ang-2, and VE-Cadherin — and vascular inflammation — sE-selectin — were found to discriminate among angioedema types.
Particularly, HAE patients had significantly higher levels of Tie-2, VE-Cadherin, and sE-selectin compared with the other two groups. In the HAE group, higher Tie-2 levels were significantly associated with lower complement C4 protein and reduced C1-INH levels and activity — known to be typically linked to HAE.
“We demonstrated for the first time that Tie-2 may be a promising biomarker candidate for HAE,” the researchers wrote.
In addition, Ang-2 levels were significantly increased in the HAE and ACE-AE groups, relative to the CSU-AE group, suggesting that “Ang-2 might be able to differentiate BK-AE from mast cell-/histamine-mediated AE,” the team wrote.
Levels of fibroblast activation protein-alpha (FAP-alpha) and tissue plasminogen activator (tPA) — two enzymes involved in the breakdown of other proteins and previously associated with inflammation — were significantly higher in all three angioedema groups compared with healthy individuals.
Taken together, “new routine clinical diagnostic criteria could not be identified,” but“Tie-2 was identified as a new promising biomarker candidate for HAE [and] FAP-[alpha] and tPA might serve as a marker for [angioedema] in general,” the researchers concluded.
Larger studies are needed to validate these findings, and the clinical utility of these potential biomarkers, they noted.