Angioedema - Pathophysiology

Pathophysiology

Bradykinin plays a critical role in all forms of hereditary angioedema. This peptide is a potent vasodilator and increases vascular permeability, leading to rapid accumulation of fluid in the interstitium. This is most obvious in the face, where the skin has relatively little supporting connective tissue, and edema develops easily. Bradykinin is released by various cell types in response to numerous different stimuli; it is also a pain mediator. Dampening or inhibiting bradykinin has been shown to relieve HAE symptoms.

Various mechanisms that interfere with bradykinin production or degradation can lead to angioedema. ACE inhibitors block ACE, the enzyme that among other actions, degrades bradykinin. In hereditary angioedema, bradykinin formation is caused by continuous activation of the complement system due to a deficiency in one of its prime inhibitors, C1-esterase (aka: C1-inhibitor or C1INH), and continuous production of kallikrein, another process inhibited by C1INH. 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.

The three types of hereditary angioedema are:

• Type I - decreased levels of C1INH (85%);
• Type II - normal levels, but decreased function of C1INH (15%);
• Type III - no detectable abnormality in C1INH, occurs in an X-linked dominant fashion and therefore mainly affects women; it can be exacerbated by pregnancy and use of hormonal contraception (exact frequency uncertain). It has been linked with mutations in the factor XII gene.

Angioedema can be due to antibody formation against C1INH; this is an autoimmune disorder. This acquired angioedema is associated with the development of lymphoma.

Consumption of foods which are themselves vasodilators, such as alcohol or cinnamon, can increase the probability of an angioedema episode in susceptible patients. If the episode occurs at all after the consumption of these foods, its onset may be delayed overnight or by some hours, making the correlation with their consumption somewhat difficult. In contrast, consumption of bromelain in combination with turmeric may be beneficial in reducing symptoms.

The use of ibuprofen or aspirin may increase the probability of an episode in some patients. The use of acetaminophen typically has a smaller, but still present, increase in the probability of an episode.