Hereditary angioedema (HAE) is an uncommon but serious genetic disease that causes swelling in various parts of the body.
Symptoms of HAE usually start in childhood and worsen during the teenage years, according to the U.S. Hereditary Angioedema Association.
People with HAE may experience episodes, or “attacks,” in which their hands, feet, face, and throat swell up. The frequency and severity of the attacks are variable. Abdominal pain, nausea, and vomiting are also common symptoms in cases where HAE affects a person’s intestinal tract.
HAE only occurs in about 1 in 10,000 to 1 in 50,000 people worldwide. Although HAE is a lifelong disease, there are treatments to help manage the condition.
HAE is caused by a variant, or defect, in the gene that makes a protein called C1 inhibitor.
This protein helps control inflammation in your body.
There are three main types of HAE:
Type 1: This is the most common form of HAE, accounting for 85 percent of all cases. People with type 1 have low C1 inhibitor levels.
Type 2: With this type, C1 inhibitor levels are normal, but the protein doesn’t work like it should. About 15 percent of occurrences are type 2.
HAE with normal C1 inhibitor: In this very rare form of HAE, formerly known as type 3, C1 inhibitor levels and function are normal. Research has found that defects in other genes — including factor XII, angiopoietin-1, and plasminogen — can cause HAE. With this type of HAE, the onset of swelling often occurs at a later age, more women are affected, and estrogen may play a role in the disease.
Each type of HAE produces similar episodes of swelling.
Hereditary angioedema can cause signs and symptoms that are scary, painful, and disfiguring.
HAE attacks cause swelling in different parts of the body. Attacks can range from mild to severe. The frequency and length of the swelling attacks varies in those with HAE. Typically, people who aren’t receiving preventive treatment for the disease have an attack about every one to two weeks. Most of these episodes last three to four days.
Your symptoms will depend on the type of HAE attack you have:
A subcutaneous attack involves swelling and redness on different areas of your skin.
If you have an abdominal episode, you might experience stomach pain, nausea, diarrhea, or vomiting.
Swelling attacks that involve the face, throat, neck, or tongue are particularly dangerous because they can interfere with breathing. These episodes are usually considered medical emergencies. You may need a breathing tube placed down your throat or into your windpipe to open your airways. Sometimes severe swelling in your throat can even lead to death.
HAE is a genetic disorder. It may be caused by changes in the SERPING1 gene (also called the C1NH gene) or in other genes, though in some cases the cause is not yet known.
These genetic variants may be inherited in an autosomal dominant pattern, meaning that it takes inheriting only one copy of the gene from a parent to have the disease. If one parent has the gene defect that causes HAE, a child has a fifty-fifty chance of inheriting it. But not all people with a genetic change will develop symptoms.
In most cases of HAE, the gene mutations mean that you either don’t have enough C1 inhibitor or it doesn’t function properly.
Not having a family history doesn’t guarantee you won’t develop HAE. The genetic variants that cause HAE can also crop up for unknown reasons during conception. In fact, as many as 25 percent of HAE cases result from a spontaneous, or “de novo,” genetic variant.
What Are the Triggers of an HAE Attack?
Sometimes, people with HAE are able to identify certain triggers that spark the swelling. Other times, these attacks come without warning.
Common triggers of HAE attacks include:
Anxiety
Stress
Minor trauma
Surgery or even dental work
Ailments such as colds or flu
Hormonal changes related to things like puberty or pregnancy
It’s important to identify the first signs of an HAE episode so that you can get treatment quickly.
It’s a good idea to keep a journal listing any potential triggers that could be causing your attacks.
Family members and close friends should know what to do if you experience an episode. Keep your medical paperwork with you in case you have a severe attack and can’t help yourself.
The U.S. Hereditary Angioedema Association’s medical advisory board also recommends that all patients keep a record of their attacks, the medicines they use, and how they respond to treatment.
There are specific blood tests used to confirm type 1 or 2 HAE, and genetic testing for HAE with normal C1-inhibitor can determine whether there is a defect in one of the genes that have been shown to also cause HAE.
Symptom onset is another key part of diagnosing HAE, and providers should ask all patients with a suspected HAE diagnosis about events leading up to the increase in symptoms. This can help providers differentiate between HAE and other conditions, such as swelling due to a drug-induced cause.
Because HAE is rare and often confused with other disorders, getting a proper diagnosis can be complicated. An average delay of 8.5 years in diagnosing HAE has been reported, and while a survey of patients with HAE found that one-third were diagnosed within a year of their first symptoms, another 32 percent of patients reported a diagnostic delay of 10 or more years.
Most experts recommend that if HAE is known to run in a family, parents wait until a child is at least 1 year old before testing them for the disease.
The age of diagnosis varies when it comes to HAE. Many people report experiencing more attacks around the time of puberty or adolescence.
Once you do get a correct diagnosis, it’s important to find a specialist who has experience working with HAE patients.
A misdiagnosis can be inconvenient and dangerous. You might not get the correct treatment, or you may have to undergo unnecessary medical procedures. Other related disorders can cause similar symptoms. These may include:
Acquired angioedema: This type of angioedema isn’t hereditary but causes swelling episodes that are similar to those of HAE. It is sometimes linked to an underlying medical condition, such as an autoimmune disorder or cancer.
Drug-induced angioedema: Some medicines can cause angioedema attacks, even if you’re not allergic to the drug. Common culprits include angiotensin-converting enzyme inhibitors, ibuprofen, and angiotensin-2 receptor blockers.
Cutis laxa: This is a rare, inherited disorder that causes limp, saggy, inelastic skin. It’s often confused with HAE.
There’s no cure for HAE, but certain therapies can help control your symptoms.
Your doctor will recommend a treatment plan based on how often you have HAE attacks, how severe the attacks are, your general health, and other factors.
All HAE patients should have access to an on-demand treatment to take when they have symptoms. Your doctor might also prescribe a preventive medicine to help protect against a future attack.
Medication Options
There are currently nine drugs approved by the U.S. Food and Drug Administration (FDA) for HAE, including preventive medications and those that treat symptoms of attacks. Additional medications are in the process of being developed.
Preventive medications include:
Andembry (garadacimab-gxii) is a once-monthly injection for people ages 12 and over.
Cinryze (C1 esterase inhibitor [human]) is indicated for adults, adolescents, and children ages 6 and older. It’s delivered intravenously and is approved for self-administration.
Dawnzera (donidalorsen) is an RNA-targeted preventive treatment for HAE that offers the longest time between doses, every four or eight weeks. It can be self-administered via auto-injector.
Heagarda (C1 esterase inhibitor subcutaneous [human]) is delivered by injection, for routine prevention of HAE attacks in patients ages 6 and older.
Orladeyo (berotralstat) is an oral, once-daily plasma kallikrein inhibitor indicated for routine prevention of attacks in patients ages 12 and older.
Takhzyro (lanadelumab-flyo) is a plasma kallikrein inhibitor (monoclonal antibody) indicated for preventing attacks in patients ages 2 and older. It’s an injection approved for self-administration.
Medications for acute attacks include:
Berinert (C1 esterase inhibitor [human]) is an IV infusion you can administer yourself. It’s approved for adults and children.
Ekterly (sebetralstat) is an oral, on-demand treatment for acute attacks in people ages 12 and older. It’s designed to treat attacks as soon as symptoms begin.
Firazyr (icatibant injection) is a bradykinin B2 receptor antagonist for treatment of acute attacks in people ages 18 and older. It’s an injection that can be self-administered.
Icatibant (generic) is an injectable bradykinin B2 receptor antagonist that treats acute attacks in people ages 18 and older.
Kalbitor (ecallantide) is indicated for treatment of acute attacks in patients ages 12 and older. It’s delivered by subcutaneous injection and it needs to be administered by a healthcare professional.
Ruconest (C1 esterase inhibitor [recombinant]) is a plasma-free recombinant C1-inhibitor concentrate for treating attacks in adults and adolescents. It’s an intravenous infusion that is approved for self-administration.
Medications like antihistamines or steroids — which are typically used to treat allergic reactions — generally won’t help an HAE episode.
Your healthcare provider can assist you in deciding on the best treatment regimen for your situation. If you have HAE, it’s important to find a doctor who’s experienced in treating the disease. Immunologists and hematologists are often trained to help people with HAE.
Some people with HAE are interested in clinical trials, which may provide a new treatment option that isn’t yet available to the general public. You can search for clinical trials at ClincalTrials.gov.
HAE is a chronic condition. Your long-term outlook will depend on the frequency, severity, and location of your HAE attacks.
While swelling episodes typically continue throughout a person’s lifetime, they can be controlled with certain treatments. And there are steps you can take to help yourself cope with the disease. Creating a support system, lowering your stress levels, and connecting with a patient advocate are just some ways to take charge of your illness. The resources and virtual support groups offered by the U.S. Hereditary Angioedema Association are a good place to start.
A serious potential complication of an HAE attack is upper airway swelling that can lead to asphyxiation. Upper airway involvement occurs in 1 to 3 percent of attacks.
A less medically urgent complication is the way HAE can affect your quality of life. Many people with HAE have three or more attacks a month and report pain, fatigue, and disfigurement following an attack. Kids may miss school, adults may have to repeatedly call in sick to work, and attacks can be unpredictable. If untreated, some attacks can last up to five days.
Hereditary angioedema is a rare genetic condition characterized by episodes of painful and extreme swelling in various body parts, most dangerously affecting the airways, which can lead to respiratory issues and require emergency medical attention.
Regular and preventive treatments, including several FDA-approved medications, are crucial in managing HAE symptoms and minimizing the frequency and severity of swelling episodes.
Diagnosis of HAE can be challenging, often taking years before an accurate assessment, which is why finding a specialist who is experienced in HAE is essential for effective management.
Triggers for HAE attacks can include stress, hormonal changes, and minor physical trauma, so identifying and recording these triggers can be beneficial in managing the condition.
