[1] The version related to histamine is due to an allergic reaction to agents such as insect bites, foods, or medications.

In severe cases, stridor of the airway occurs, with gasping or wheezy inspiratory breath sounds and decreasing oxygen levels.

Patients with HAE can also have recurrent episodes (often called "attacks") of abdominal pain, usually accompanied by intense vomiting, weakness, and in some cases, watery diarrhea, and an unraised, nonitchy splotchy/swirly rash.

Abdominal attacks have also been known to cause a significant increase in the patient's white blood cell count, usually in the vicinity of 13,000 to 30,000.

HAE may also cause swelling in a variety of other locations, most commonly the limbs, genitals, neck, throat and face.

[5] This peptide is a potent vasodilator and increases vascular permeability, leading to rapid accumulation of fluid in the interstitium.

This serine protease inhibitor (serpin) normally inhibits the association of C1r and C1s with C1q to prevent the formation of the C1-complex, which - in turn - activates other proteins of the complement system.

Additionally, it inhibits various proteins of the coagulation cascade, although effects of its deficiency on the development of hemorrhage and thrombosis appear to be limited.

Consumption of foods that are themselves vasodilators, such as alcoholic beverages or cinnamon, can increase the probability of an angioedema episode in susceptible patients.

Mast cell tryptase levels may be elevated if the attack was due to an acute allergic (anaphylactic) reaction.

HAE type III is a diagnosis of exclusion consisting of observed angioedema along with normal C1 levels and function.

[citation needed] The hereditary form (HAE) often goes undetected for a long time, as its symptoms resemble those of more common disorders, such as allergy or intestinal colic.

An important clue is the failure of hereditary angioedema to respond to antihistamines or steroids, a characteristic that distinguishes it from allergic reactions.

The former is used during the reaction cascade in the complement system of immune defense, which is permanently overactive due to the lack of regulation by C1-INH.

Edema of the gastrointestinal mucosa typically leads to severe abdominal pain; in the upper respiratory tract, it can be life-threatening.

[11] The pathogenesis of this disorder is suspected to be related to unopposed activation of the contact pathway by the initial generation of kallikrein and/or clotting factor XII by damaged endothelial cells.

The end product of this cascade, bradykinin, is produced in large amounts and is believed to be the predominant mediator leading to increased vascular permeability and vasodilation that induces typical angioedema "attacks".

[18][19] In hereditary angioedema (HAE), specific stimuli that have previously led to attacks may need to be avoided in the future.

In 2018, the U.S. Food and Drug Administration approved lanadelumab, an injectable monoclonal antibody, to prevent attacks of HAE types I and II in people over age 12.

Lanadelumab inhibits the plasma enzyme kallikrein, which liberates the kinins bradykinin and kallidin from their kininogen precursors and is produced in excess in individuals with HAE types I and II.

[24][25] In the U.S., there are as many as 80,000 to 112,000 emergency department (ED) visits for angioedema annually, and it ranks as the top allergic disorder resulting in hospitalization.