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There are two different subtypes(2) of HAE based on the underlying genetic defect in the control of the blood protein C1-esterase inhibitor:
• Type I HAE: This subtype is characterized by decreased levels of functional C1-INH protein. About 80-85% of patients suffer from this form of the disease.
• Type II HAE: This type is associated with normal or increased levels of a dysfunctional C1-INH protein resulting in reduced levels of C1-INH activity.
• Type III HAE: Recently a type III has been postulated: HAE type III arises independently of a C1-INH deficiency. It is relatively rare and primarily affects women. In some patients a mutation of factor XII was found.(15, 16-18)
Hereditary angioedema of type I and type II is caused by a defect (mutation) in the gene responsible for producing the protein C1 esterase inhibitor (C1-INH). Unlike other hereditary diseases, the healthy gene cannot compensate for the defect in the other gene in patients with HAE. Therefore, a child has a 50% chance of developing HAE if one parent has the gene mutation.(2,14)
Under normal conditions, C1-INH regulates the body’s production of bradykinin, a locally acting hormone that plays an important role in the control of the dilation (widening) and permeability of blood vessels – for example, in response to an injury or infection. If the C1-INH is not functioning properly or if its concentration is decreased, bradykinin is released excessively resulting in local swellings (edema).
Besides the contact system, C1-INH is also involved in the so called complement system which is part of the immune defense. As in the contact system, an external stimulus, for example a foreign body or microbe, triggers a reaction cascade which aims to eliminate the alien.
The cascade starts with the protein C1, whose direct counterpart is C1-INH. C1 is activated as soon as the immune system detects a foreign body, although the process is also self-activating to a lesser extent. Activated C1 activates a series of other factors in the complement system resulting in the elimination of the pathogen.
Infections, injuries, operations or stress(8) may lead to consumption of C1-INH and may thus result in elevation of bradykinin levels with subsequent edema formation. Drugs that lower blood pressure (ACE inhibitors) can also cause edema: by inhibiting the degradation of bradykinin its level is increased.
Bradykinin is a naturally occurring peptide hormone that consists of nine amino acids and is formed locally in tissue. It is involved in the mediation of pain in the event of injury or inflammation. It increases the permeability of the vessels, dilates the blood vessels and causes smooth muscle to contract. In hereditary angioedema, bradykinin is the key mediator for the development of swelling.
It is part of a blood coagulation subsystem known as the contact system, which is regulated by C1-INH. If bradykinin levels are increased, fluids will pass through the vessel walls into the surrounding tissue causing the local swelling of an HAE attack.
After activation of the contact system by an external stimulus like an injury, a complex cascade of different steps follows ending up in the release of bradykinin. Main factors within the contact system are the factor XII and kallikrein.
Finally, after binding to the bradykinin receptor, bradykinin triggers a series of reactions in the tissues(19-23):
• Bradykinin increases the permeability of the vessels (vascular permeability), which allows liquid to pass into the tissues and therefore causes edema.
• Bradykinin widens the blood vessels (vasodilatation) and lowers blood pressure.
• Bradykinin causes the smooth muscle in the tissues to contract, producing cramps and pain.
C1-INH can normally inhibit (stop) the reaction cascade at two points: by preventing self-activation of factor XII and by inhibiting the release of bradykinin from HMW kininogen. In case of C1-INH deficiency release of bradykinin is no longer efficiently controlled. Bradykinin levels increase and edema develops.