People with hereditary angioedema (HAE) experience episodes of soft tissue swelling. Such instances occur in the hands, feet, gastrointestinal tract, genitals, face, and throat.
During an HAE attack, one’s inherited genetic mutation results in a cascade of events that lead to swelling. The swelling is very different from an allergy attack.
Mutations occur in the SERPING1 gene
Inflammation is your body’s normal response to infection, irritation, or an injury.
At some point, your body needs to be able to control the inflammation because too much can lead to problems.
There are three different types of HAE. The two most common types of HAE (types 1 and 2) are caused by mutations (errors) in a gene called SERPING1. This gene is located on chromosome 11.
This gene provides instructions for making the C1 esterase inhibitor protein (C1-INH). C1-INH helps with reducing inflammation by blocking the activity of proteins that promote inflammation.
C1 esterase inhibitor levels are reduced in amount or function
The mutation that causes HAE can lead to a reduction in C1-INH levels in the blood (type 1). It can also result in a C1-INH that doesn’t function properly, despite a normal level of C1-INH (type 2).
Something triggers a demand for C1 esterase inhibitor
At some point, your body will need C1-INH to help control inflammation. Some HAE attacks happen for no clear reason. There are also triggers that increase your body’s need for C1-INH. The triggers vary from person to person, but common triggers include:
- repetitive physical activities
- activities that create pressure in one area of the body
- freezing weather or changes in weather
- high exposure to the sun
- insect bites
- emotional stress
- infections or other illnesses
- dental procedures
- hormonal changes
- certain foods, like nuts or milk
- blood pressure-reducing medications, known as ACE inhibitors
If you have HAE, you don’t have enough C1-INH in your blood to control inflammation.
Kallikrein is activated
The next step in the chain of events leading to an HAE attack involves an enzyme in the blood known as kallikrein. C1-INH suppresses kallikrein.
Without enough C1-INH, kallikrein activity isn’t inhibited. The kallikrein then cleaves (separates) a substrate known as high-molecular-weight kininogen.
Excessive amounts of bradykinin are produced
When kallikrein splits kininogen, it results in a peptide known as bradykinin. Bradykinin is a vasodilator, a compound that opens up (dilates) the lumen of blood vessels. During an HAE attack, excessive amounts of bradykinin are produced.
The blood vessels leak too much fluid
Bradykinin allows more fluid to pass through blood vessels into body tissues. This leakage and the blood vessel dilation it causes also results in lower blood pressure.
Fluid accumulates in the body tissues
Without enough C1-INH to control this process, fluid builds up in the body’s subcutaneous tissues.
The excess fluid results in the episodes of severe swelling seen in people with HAE.
What happens in type 3 HAE
A third, very rare type of HAE (type 3), happens in a different matter. Type 3 is the result of a mutation in a different gene, located on chromosome 5, called F12.
This gene provides instructions for making a protein called coagulation factor XII. This protein is involved in blood clotting and also responsible for stimulating inflammation.
A mutation in the F12 gene creates a factor XII protein with increased activity. This in turn causes more bradykinin to be produced. Like types 1 and 2, the increase in bradykinin makes blood vessel walls leak uncontrollably. This leads to episodes of swelling.
Treating the attack
Knowing what happens during an HAE attack has led to improvements in treatments.
To stop fluid from building up, people with HAE need to take medication. HAE drugs either prevent swelling or increase the amount of C1-INH in the blood.
- a direct infusion of donated fresh frozen plasma (which contains C1 esterase inhibitor)
- medications that replace C1-INH in the blood (these include Berinert, Ruconest, Haegarda, and Cinryze)
- androgen therapy, such as a drug called danazol, which can increase the amount of C1-INH esterase inhibitor produced by your liver
- ecallantide (Kalbitor), a medication that inhibits cleavage of kallikrein, thus preventing the production of bradykinin
- icatibant (Firazyr), which stops bradykinin from binding to its receptor (bradykinin B2 receptor antagonist)
As you can see, an HAE attack occurs differently from an allergic reaction. Drugs used to treat allergic reactions, like antihistamines, corticosteroids, and epinephrine, won’t work in an HAE attack.