Hereditary Angioedema: C1 Esterase Inhibitor

Hereditary angioedema (HAE) is an autosomal dominant disorder caused by deficiency (type I, ~85%) or dysfunction (type II, ~15%) of C1 esterase inhibitor (C1-INH), a serine protease inhibitor (serpin) that regulates multiple protease cascades. C1-INH normally inhibits kallikrein in the contact activation (kinin-bradykinin) system, C1r and C1s in the complement system, and factor XIIa in the coagulation system. When C1-INH is deficient or dysfunctional, unregulated kallikrein activity generates excessive bradykinin from high-molecular-weight kininogen (HMWK). Bradykinin binds to B2 receptors on vascular endothelial cells, increasing vascular permeability by disrupting endothelial cell junctions via activation of nitric oxide and prostacyclin pathways. This produces the hallmark of HAE: recurrent episodes of non-pitting, non-pruritic, subcutaneous or submucosal edema lasting 2-5 days without urticaria. Critical distinction: HAE is bradykinin-mediated, NOT histamine-mediated — therefore it does NOT respond to antihistamines, corticosteroids, or epinephrine (unlike allergic/histaminergic angioedema). Attacks involve the face (lips, eyelids), extremities, genitalia, and GI tract (abdominal attacks mimicking acute abdomen with severe pain, vomiting, diarrhea). Laryngeal attacks are the most dangerous complication, potentially causing fatal airway obstruction. HAE type III (rare, predominantly affects women)...