What is the pathophysiology of acquired angioedema (AAE) due to C1 inhibitor (C1-INH) deficiency (C1-INH-AAE)?

Updated: May 20, 2020
  • Author: Amanda T Moon, MD; Chief Editor: William D James, MD  more...
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Answer

C1-INH is a multifunctional serine protease inhibitor that is normally present in high concentrations in plasma. It is primarily synthesized by hepatocytes. Its synthesis is up-regulated by interferon-gamma, interleukin 6, and interleukin 1. Androgens may also have a role in stimulating C1-INH synthesis. The major functions of C1-INH include inhibition of activated C1r and C1s, inhibition of activated Hageman factor (XIIa), and inhibition of activated kallikrein, the contact system protease that cleaves kininogen and releases bradykinin. [2]

Bradykinin is an important mediator involved in tissue permeability and vascular dilatation. Its biological effect is exerted through activation of bradykinin B2 receptors, which are expressed in the membranes of endothelial and smooth muscles cells. Elevated blood bradykinin levels are found during clinical flares in patients with angioedema.  Other kinins may also be pathogenic. [2]

The specific trigger responsible for inducing the release of these vasoactive peptides is unclear. Activation of factor XII (Hageman factor) may be secondary to phospholipid release from damaged or apoptotic cells and may be important in the generation of bradykinin from endothelial activation. This hypothesis encompasses the role of illness or tissue injury in the generation of bradykinin.

Supporting the importance of bradykinin in acquired angioedema, vascular permeability has been shown to increase in mice deficient in C1-INH, but not in mice with a deficiency in both C1-INH and the bradykinin B2 receptor. [3] The precise pathophysiology of acquired angioedema type I remains to be defined. C1-INH levels diminish as a result of its increased catabolism and excessive activation of the classic complement pathway.


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