Disease causes

Although the consequences are ultimately the same, there are three different subtypes of HAE based on the underlying genetic defect:

• Type I HAE: In this subtype, the gene mutation causes the body to produce insufficient amounts of C1-INH. About 85% of patients suffer from this form of the disease.
• Type II HAE: In this case, although sufficient C1-INH is produced, the protein produced by the defective gene is unable to function.
• Type III HAE: To date, this very rare form of the disease has been observed in women and men. Unlike the other two subtypes of HAE, this subtype is not associated with a C1-INH deficiency and research into the exact causes is ongoing.

In most cases hereditary angioedema of type I and type II is caused by a paternally or maternally inherited defect (mutation) in one of the two copies of the gene jointly 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 (known as an autosomal dominant hereditary disease). A child has a 50% chance of developing HAE if one parent has the gene mutation.

The lack of functioning C1-INH causes tissue edema, primarily through increased release of the small protein molecule (peptide) bradykinin. C1-INH can normally inhibit the reaction cascade at two points: by preventing self-activation of factor XII and by inhibiting the release of bradykinin from HMW kininogen. If there is a C1-INH deficiency, these processes are not controlled and local bradykinin concentration may increase to a critical level if additional triggers are present. As a result edema develops.

Besides the contact system, a system known as the complement system of immune defence also contributes to the development of edema. As in the contact system, an external stimulus, in this case 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 triggers a series of other factors in the complement system. These either attack the alien directly or, like factor C4, an important factor for diagnosis of HAE, lead to a bradykinin mediated increase in vascular permeability and therefore the development of oedema. If there is a C1-INH deficiency, C1 activation cannot be regulated, which encourages the development of swelling.

The mechanisms described above also explain why episodes of HAE often occur as a result of infections, injuries, operations or stress. Drugs that lower blood pressure (ACE inhibitors) can also cause edema: the levels of bradykinin are held at raised levels as ACE inhibitors slow the natural degradation of bradykinin.

The role of bradykinin in edema formation