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Research Article: Associations of hereditary angioedema attacks with intestinal permeability and inflammatory cytokines

Date Published: 2026-08-10

Abstract:
Hereditary angioedema (HAE) is characterized by recurrent subcutaneous and submucosal edema. Gastrointestinal involvement is common; however, the role of intestinal barrier dysfunction and its relationship with systemic inflammation in HAE remains poorly understood. This cross-sectional study included 169 patients with HAE. Circulating markers of intestinal permeability (e.g., lipopolysaccharide [LPS] and fatty acid–binding protein 2 [FABP2]) and inflammatory cytokines (e.g., interleukin [IL]-1?, IL-6, IL-10, and tumor necrosis factor-?) were measured. Associations with edema location and the HAE activity score (HAE-AS) were evaluated through univariate and multivariable regression models. Exploratory mediation and interaction analyses were performed to assess potential relationships among LPS, IL-6, and gastrointestinal edema. Relative to patients without recent gastrointestinal edema, those with recent gastrointestinal edema had significantly higher serum levels of LPS and IL-6 (P = 0.030 and P = 0.031, respectively); FABP2 levels did not significantly differ. Multivariable logistic regression showed that LPS (odds ratio = 3.90, 95% CI: 1.58-10.35, P = 0.004) and IL-6 (odds ratio = 1.15, 95% CI: 1.01-1.31, P = 0.038) were independently associated with recent gastrointestinal edema. No significant mediation or interaction between LPS and IL-6 was observed. Linear regression analysis indicated that LPS was independently associated with HAE-AS (? = 1.499, P = 0.046). Altered intestinal permeability and inflammatory activation, particularly elevated LPS levels, are closely associated with gastrointestinal manifestations and disease activity in HAE. These findings suggest a gut–angioedema axis contributes to phenotype-specific disease expression. IL-6 may reflect concurrent inflammatory activation; the absence of elevated FABP2 suggests that gastrointestinal edema can occur without overt epithelial injury. These results support a role for the gut environment in shaping disease heterogeneity and provide a basis for further mechanistic studies.

Introduction:
Hereditary angioedema (HAE) is characterized by recurrent subcutaneous and submucosal edema. Gastrointestinal involvement is common; however, the role of intestinal barrier dysfunction and its relationship with systemic inflammation in HAE remains poorly understood.

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