Blood marker may be clue to identifying idiopathic angioedema
Lower FAP levels distinguish condition from other angioedema forms
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HAE attacks
Lower blood levels of an enzyme involved in processes such as tissue remodeling and wound healing may help distinguish people with idiopathic angioedema, a form of angioedema that has no obvious cause, from those with hereditary angioedema (HAE) or mast cell-mediated angioedema, a small study in China suggested.
Levels of the enzyme, fibroblast activation protein (FAP), were significantly lower in the blood of people classified as having idiopathic angioedema than in those with either of the other two forms of angioedema and in healthy people. “Lower FAP levels may represent an exploratory biomarker candidate” for distinguishing idiopathic angioedema from other angioedema types, the researchers said.
However, they emphasized that idiopathic angioedema is not a single disease with a single underlying cause. Instead, the diagnosis is made after known causes have been excluded, meaning the group may include people who may ultimately be reclassified as mechanisms behind their swelling become better understood. The findings, therefore, “should be interpreted as hypothesis-generating,” the researchers wrote.
The study, “Analyzing the clinical profile and potential biomarkers to differentiate idiopathic angioedema from hereditary or mast cell-mediated angioedema,” was published in the World Allergy Organization Journal.
Angioedema refers to swelling in the deeper layers of the skin or tissues lining internal organs. It occurs when small blood vessels become more permeable, allowing fluid to leak into surrounding tissues. Attacks can affect areas such as the face, lips, hands and feet, abdomen, and upper airway.
Different forms, different treatments
HAE is caused by genetic mutations that lead to excessive production of bradykinin, a signaling molecule that increases blood vessel permeability. In mast cell-mediated angioedema, swelling results from the activation of mast cells, immune cells involved in allergic and inflammatory responses, and may occur alongside itchy, raised welts or hives.
Identifying the cause of swelling is important because different forms of angioedema require different angioedema treatments. Yet in some people with recurrent angioedema, no established cause can be identified. These cases are classified as idiopathic angioedema, referred to as AE-UN in the study.
The biological mechanisms underlying AE-UN remain poorly understood, and there is no established treatment approach, which can make managing acute attacks particularly challenging. Reliable biomarkers that can distinguish AE-UN from HAE and mast cell-mediated angioedema are also lacking, the researchers wrote.
To better characterize people currently classified as having AE-UN, the team recruited 56 adults aged 18 to 70 with recurrent angioedema at Peking Union Medical College Hospital in China between January 2023 and March 2025.
Sixteen had AE-UN, 20 had HAE type 1 or 2, and 20 had mast cell-mediated angioedema. Another 24 age- and sex-matched people without angioedema served as healthy controls.
The groups differed in some of their clinical characteristics. Disease duration was significantly shorter in people with AE-UN than in those with HAE, at a mean of 2.26 years vs. 15.78 years, but did not differ significantly from the 3.02 years reported with mast cell-mediated angioedema. A family history of angioedema was reported by 90% of people with HAE, but none of those in the other two groups.
In the AE-UN group, the face was the most commonly affected site, reported in 68.75% of participants. Four of the 16 people with AE-UN (25%) experienced potentially life-threatening swelling involving upper-airway sites — the uvula, throat, or larynx. Such upper-airway swelling occurred in 10% of those with mast cell-mediated angioedema and 65% of those with HAE.
Hives were also significantly more common with mast cell-mediated angioedema, affecting 70% of that group versus 18.75% of those with AE-UN and 5% of those with HAE.
The researchers measured several blood proteins involved in inflammation and blood vessel function, looking for differences that might help distinguish the three forms of angioedema and provide clues about the mechanisms underlying their swelling.
The clearest difference involved FAP. Its levels were significantly lower in people with AE-UN than in those with mast cell-mediated angioedema, HAE, or healthy controls. In contrast, FAP levels did not differ significantly between participants in the HAE and mast cell-mediated groups.
Other findings pointed to biological changes that may be shared across angioedema types. Levels of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and their receptor Tie-2, proteins involved in regulating blood vessel stability and permeability, were significantly higher in the angioedema groups than in healthy controls, but did not differ significantly among the three angioedema types.
“Decreased FAP may serve as a promising exploratory biomarker candidate in this selected AE-UN [patient population], while Ang-1, Ang-2, and Tie-2 may represent general markers of angioedema,” the researchers wrote.
Still, they noted that “AE-UN remains a heterogeneous, exclusion-based category,” and the findings do not establish FAP as a definitive diagnostic biomarker or AE-UN as a single disease.
“Larger multicenter studies [incorporating] comprehensive genetic testing and longitudinal follow-up are needed before these observations can be translated into clinical practice,” the team concluded.
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