Hereditary angioedema classification: Expanding knowledge by genotyping and endotyping

Abstract

Hereditary angioedema (HAE) encompasses a group of diseases characterized by recurrent, genetically mediated angioedema associated with increased vascular permeability primarily due to bradykinin. The disease poses diagnostic challenges, leading to underdiagnosis and delayed therapy. Severe manifestations include laryngeal and intestinal angioedema, contributing to significant morbidity and mortality. If left undiagnosed, the estimated mortality rate of the disease ranges from 25% to 40% due to asphyxiation caused by laryngeal angioedema. There is a pressing need to enhance awareness of hereditary angioedema and its warning signs. The acronym "H4AE" may facilitate the memorization of these signs. This study comprehensively reviews clinical, laboratory, and physiopathological features of documented HAE subtypes. The study advocates for an improved HAE classification based on endotypes, building on the knowledge of angioedema pathophysiology. The proposed endotype classification of HAE offers a clear and applicable framework, encouraging advancements in disease understanding and classification.

Keywords: Angioedema pathophysiology; Bradykinin; C1 inhibitor deficiency; Classification; Disease awareness; Endotype; Genetic mutations; H4AE; Hereditary angioedema; Intestinal angioedema; Laryngeal angioedema; Morbidity and mortality; Phenotype; Vascular permeability.

Fig. 1

“H4AE” (HAAAAE): Warning signs of Hereditary Angioedema

Fig. 2

Pathophysiology of recurrent angioedema with its endotypes and mediators. The mechanisms proposed in this figure partially represent hypotheses and should be interpreted with caution. While supported by existing scientific evidence, further research is needed to fully validate these findings. The figure illustrates the pathophysiology of HAE-C1INH and HAE-nC1INH with its seven endotypes. B2r: bradykinin receptor B2; VEGF: vascular endothelial growth factor; VEGFr2: VEGF receptor 2; TIE2: tunica interna endothelial cell kinase 2; H1r: histamine receptor H1; HAE-C1INH: HAE due to C1INH deficiency; HAE-nC1INH: HAE with normal C1INH; HAE-ANGPT: HAE due to Angiopoietin 1; HAE-CPN: HAE due to carboxypeptidase N; HAE-FXII: HAE due to FXII mutation; HAE-HSST: HAE due to Heparan sulfate 3-O-sulfotransferase; HAE-KNG: HAE due to kininogen 1 mutation; HAE-MYOF: HAE due to myoferlin mutation; HAE-PLG: HAE due to plasminogen mutation

Fig. 3

Endotype Classification of Recurrent Angioedemas. The mechanisms proposed in this figure partially represent hypotheses and should be interpreted with caution. While supported by existing scientific evidence, further research is needed to fully validate these findings. ∗ In the figure, HAE-ANGPT is positioned in both the Bradykinin-mediated and VEGF-mediated endotypes because angiopoietin inhibits the actions of both bradykinin and VEGF. ∗∗ About 30% of patients experience NSAIDS exacerbated disease. ∗∗∗Other drugs: neuromuscular blocking agents, quinolones, iodine contrast media, opioids, vancomycin, among others. VEGF: vascular endothelial growth factor; HAE: hereditary angioedema; C1INH: C1-inhibitor; HAE-C1INH: HAE due to C1INH deficiency; HAE-nC1INH: HAE with normal C1INH; HAE-ANGPT: HAE due to Angiopoietin 1; HAE-CPN: HAE due to carboxypeptidase N; HAE-FXII: HAE due to FXII mutation; HAE-HSST: HAE due to Heparan sulfate 3-O-sulfotransferase; HAE-KNG: HAE due to kininogen 1 mutation; HAE-MYOF: HAE due to myoferlin mutation; HAE-PLG: HAE due to plasminogen mutation; AAE-C1INH: acquired angioedema with C1–INH deficiency; ACEi: angiotensin converting enzyme inhibitor; DPP4: dipeptidyl peptidase IV inhibitors; tPA: tissue plasminogen activator