Biomarkers in Hereditary Angioedema: From Bench to Bedside

Hereditary angioedema (HAE) is a rare disorder characterized by recurrent episodes of subcutaneous and/or submucosal swelling. Advances in molecular and translational research have identified novel genetic, biochemical, and immunological biomarkers that refine disease classification and help explain marked clinical heterogeneity.

In HAE due to C1 inhibitor deficiency HAE-C1INH, caused by pathogenic variants in SERPING1, the core diagnostic biomarker profile includes low C4 and reduced C1INH concentration and/or function. Nonetheless, substantial variation in age at onset, attack frequency, and severity among individuals with similar causal variants underscores the influence of modifier genes, hormonal factors, and environmental triggers. Emerging biomarkers that may better reflect disease activity and pathophysiology include SERPING1 variant type and promoter changes (e.g., c.-21T>C), modifiers in the F12 and CC2D2B, and biochemical measures of contact system activation such as stimulated kallikrein activity, cleaved high molecular-weight kininogen, and activated factor XII. Inflammatory cytokines further suggest endothelial dysfunction and systemic inflammatory amplification during attacks.

HAE with normal C1INH (HAE-nC1INH) is rarer and diagnostically challenging because routine laboratory markers, including C4 and C1INH, and most standard biochemical/immunologic tests are typically within the normal range, leaving diagnosis heavily dependent on clinical features and targeted genetic evaluation. Pathogenic variants in F12, PLG, KNG1, ANGPT1, MYOF, HS3ST6, CPN1, and DAB2IP explain a subset of cases, but many remain genetically unresolved (HAE unknown type [UNK]), implying additional contributors. Estrogen sensitivity and dysregulated fibrinolytic/endothelial pathways are particularly relevant. Candidate biomarkers proposed for HAE-UNK include variants in XPNPEP2 and BDKRB1, as well as circulating markers such as galectin-3, IL-17A, E-selectin, and VE-cadherin, consistent with inflammation-driven endothelial barrier disruption.

Current research emphasizes multi-omics profiling and functional assays to improve diagnostic precision, patient stratification, and monitoring. Collectively, novel biomarkers provide mechanistic insight into bradykinin overproduction, endothelial permeability, and systemic inflammation, offering opportunities for personalized therapeutic approaches and improved disease monitoring across HAE subtypes.