Hereditary angioedema, or HAE, is a chronic genetic disease characterized by sudden but temporary swelling attacks affecting the deeper layers of the skin that usually appear on their own, without hives or a rash.
In severe cases, the condition can become life-threatening and require immediate medical attention.
This type of angioedema is estimated to affect one in 50,000 to 150,000 individuals worldwide.
HAE is passed on from parent to child as an autosomal dominant trait, meaning only one parent has to have the disease to pass it on. There is a 50% risk that a parent with the condition will pass it to their children.
There are three types of HAE. Though they involve different genes, all three share a common basic cause: an overproduction of bradykinin, which regulates blood pressure and inflammation by promoting blood vessels to dilate or widen. Angioedema swelling occurs when bradykinin is activated in the deep layers of the skin, allowing fluid to flow from the bloodstream into nearby tissues.
HAE types 1 and 2 are caused by mutations in the SERPING1 gene, which carries instructions for making a protein called C1-inhibitor (C1-INH). This protein blocks the activity of two other proteins — plasma kallikrein and coagulation factor 12, both of which promote the production of bradykinin. When there isn’t enough C1-INH available to stop them, bradykinin levels can get too high and cause an attack.
Mutations can occur anywhere in the gene and prevent the production of C1-INH (HAE type 1) or in a very specific region of the gene called exon 8, which causes a less-effective C1-INH protein to be produced (HAE type 2).
HAE type 3 is caused by mutations in another gene called F12, which provides instructions for making coagulation factor 12, which plays a crucial role in blood clotting and inflammation. Mutations in HAE type 3 cause this protein to be overactive and stimulate the inflammatory response more than usual. In response, the body produces more bradykinin, causing periodic swelling attacks.
HAE can occur anywhere on the body, though the lips, hands, feet, and the skin around the eyes are the most common sites. Swelling episodes usually begin in childhood and may also occur in the mucosal linings of the respiratory and digestive tracts. They normally disappear on their own after three to four days. Symptoms also tend to worsen at puberty.
Swelling attacks happen regularly, often without a trigger, averaging once a week or every two weeks when untreated. They can also be triggered by injury, stress, pain, viral infections, and some medical and dental procedures, including surgery.
The frequency and severity of the swellings depend on the individual and can vary significantly even among members of the same family. As such, it is recommended that people be genetically tested if they have a family of history of chronic and recurring swelling episodes, intestinal pain and nausea, sudden and unexplained death, or HAE.
Swelling in the mouth, throat, or intestines can cause serious health problems. When severe swelling occurs in the intestines, the individual may experience nausea, vomiting, and intense pain. In the mouth and throat, severe swelling can cause pain and difficulty in swallowing, speaking, and breathing. Breathing difficulties can quickly become life-threatening emergencies and require immediate treatment.
HAE swellings usually do not respond effectively to allergy medications or steroids. More effective medications for HAE include C1-INH boosting medications.
Berinert, a plasma-derived C1-INH concentrate, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute abdominal attacks and facial swelling related to HAE. Kalbitor (ecallantide) is an injectable therapy used to treat sudden and potentially life-threatening swelling attacks in HAE patients ages 12 or older.
Cinryze, also a C1-INH therapy, is used for routine prevention (prophylaxis) of spontaneous swelling attacks in children, adolescents, and adults. Ruconest and Haegarda, both recombinant C1-INH, are used for the treatment and prevention of acute attacks.
A once-daily oral therapy called Orladeyo (berotralstat) has also been approved to prevent attacks in patients aged 12 years and older.
In life-threatening situations, where swelling in the throat or mouth has blocked the airway and the individual is having trouble breathing, an EpiPen (epinephrine) or Firazyr (icatibant) can be used.
If treatments are ineffective, immediate physical intervention may be needed to ensure that patients continue breathing. In such cases, a temporary surgical opening in the throat (tracheotomy) may be created and oxygen may have to be supplied.
To avoid episodes of angioedema associated with surgery, dental work, and similar stresses, short-term treatment is suggested before surgery or dental procedures. Patients should discuss options with their physicians.
Last updated: Jan. 6, 2022, by Teresa Carvalho MS
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