Hereditary angioedema: Looking for bradykinin production and triggers of vascular permeability

Abstract

Since the Osler's identification of the inherited nature of hereditary angioedema, a huge array of information was collected on pathogenetic mechanisms of the disease. Over the last years, information grew fast, and mutations in different genes, in addition to C1‐inhibitor, were found to be causative. All types are inherited as autosomal‐dominant traits with incomplete penetrance and little or no genotype‐phenotype correlation. As a result, the clinical expression is characterized by a large heterogeneity. The acknowledgement of mechanisms leading to heterogeneity of the clinical phenotype is likely to provide important information not only for a better understanding of the pathogenesis but also for therapy. Regardless of which gene is mutated, similar pathways seem to play a pivotal role, triggering the up‐regulation of contact activation system/kallikrein kinin system and giving rise to an unbalanced increase of bradykinin. However, notwithstanding the increase of bradykinin in bloodstream, the phenomenon is localized and no general vascular leakage and oedema is recognized. Thus, it is conceivable that there exist one or more localized factors that stimulate the production of bradykinin, which does not become a systemically event. Uncovering of these factors may shed lights on the missing part of the pathogenesis of hereditary angioedema. The present review, collecting information on pathogenesis from biochemical and genetics investigations, tries to provide a comprehensive view of the pathogenesis of hereditary angioedema. This can allow for a better understanding of the disease and lead to focused investigations that can further improve our knowledge.

Gut microbiome alterations in hereditary angioedema

“…Predictive functional profiling of microbial communities was consistent with the above findings. Luminal expansion of Proteobacteria was also observed in humans with irritable bowel syndrome [43][44] , inflammatory bowel disease [45][46][47] , necrotizing enterocolitis 9 and colorectal cancer [48][49] , and may represent a marker of the destruction of intestinal epithelial barriers and induction of gut inflammation. Decreased Proteobacteria abundance was observed among patients with HAE taking danazol or tranexamic acid, and thus may represent a useful marker for therapeutic evaluation in clinical practice.…”

“…Ample evidence has shown that HAE has variable clinical features, with significant interindividual diversity in triggers, prodromal signs, age at first onset, attack frequency, attack severity, and edema locations 24 . Numerous studies have investigated the mechanisms underlying phenotypic diversity and the triggers for vascular leakage 9,[25][26][27] .…”

“…Patients with mild disease may only have occasional and transient swelling of extremities, while patients with severe disease may experience excruciating pain, vomiting, diarrhea, intestinal edema, dyspnea, and asphyxia secondary to laryngeal attacks 8 . The factors underlying clinical heterogeneity remain unclear 9 . Patients carrying identical mutations can have variable symptoms, even among siblings 9 .…”

“…The factors underlying clinical heterogeneity remain unclear 9 . Patients carrying identical mutations can have variable symptoms, even among siblings 9 . No reliable biomarkers, including C4 and C1-INH antigen levels, have been able to accurately predict HAE severity and frequency or evaluate the therapeutic effects of interventions.…”

The FXII c.-4T>C Polymorphism as a Disease Modifier in Patients With Hereditary Angioedema Due to the FXII p.Thr328Lys Variant

“…Clinical variability and incomplete penetrance are still challenging characteristics for the diagnosis of the different HAE variant forms recognized to date. Although a major influence of environmental factors is evident (as exemplified by estrogen exposure in the case of HAE-FXII patients), part of the variability can also be ascribed to disease-modifying genes ( Margaglione et al, 2019 ). Most of the HAE disease-modifiers identified are related with changes in the plasma activity of bradykinin catabolic enzymes.…”