Is It Hereditary Angioedema or Allergic Angioedema?

Hereditary angioedema (HAE) is a genetic condition that causes bouts of swelling in the tissue under your skin. The uncomfortable swelling can happen in many different parts of your body, including your hands, feet, genitals, mouth, and eyes, as well as in your gastrointestinal tract, throat, and airways.

Knowing which one you’re dealing with can make all the difference in finding the right treatment and avoiding a life–threatening health crisis.

Both conditions can cause the same distressing symptom: swelling (angioedema).

• Eyelids
• Lips
• Tongue
• Throat and airways
• Hands
• Feet
• Genitals

“There are a few key differences in how the conditions present,” says Timothy Craig, DO, a professor of medicine and an allergy and immunology researcher at Penn State Health in Hershey, Pennsylvania.

Histamine-mediated (or allergic) angioedema often causes redness, itchiness, and sometimes hives, Dr. Craig says.

Although swelling related to HAE can look red, it’s typically not itchy, rarely has hives, and lasts longer — a few days rather than hours, he says.

Both types of angioedema can be serious if swelling affects your airways. Throat or tongue swelling, often accompanied by a hoarse voice, or any trouble breathing are medical emergencies that require immediate treatment.

Symptoms usually start in childhood or adolescence and can worsen around puberty.

Common triggers or contributing factors include:

• Physical injury or minor trauma (including dental work)
• Emotional stress
• Infections, such as a cold or flu
• Hormonal changes (such as those related to the menstrual cycle or pregnancy)
• Certain activities like heavy exercise or typing

Histamine- or mast cell–mediated angioedema results from the release of histamine and other chemicals from cells in your skin. These substances cause itching, hives, and swelling.

Allergic angioedema isn’t always the most accurate label, Craig says.

“I like the term ‘histamine-induced’ or ‘mast cell–induced’ rather than ‘allergic,’ because the term ‘allergic’ makes you think it’s a reaction to foods or drugs. While that can be true, many cases have no allergic component per se and are spontaneous,” he says.

Triggers can include:

• Foods such as eggs, nuts, shellfish, or dairy
• Medications like antibiotics and pain relievers
• Insect bites or stings
• Autoimmune diseases such as lupus

Diagnosis of any type of angioedema starts with taking a thorough medical history.

In addition to giving you a physical exam, your healthcare provider will ask questions that may include:

• How quickly does the swelling develop?
• How long does the swelling last?
• Is it itchy?
• Do you get hives?
• Does anyone in the family have similar symptoms?
• What medications are you taking?
• Have you noticed what triggers or precedes the swelling?

From there, your doctor may order specific tests:

• For suspected HAE, your doctor may order blood tests that measure C4 levels and C1-inhibitor levels and function. C4 is a protein that may be low in people with HAE. Genetic testing can confirm certain rare subtypes.

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• For suspected histamine- or mast cell–mediated angioedema, your doctor might recommend skin or blood testing for allergies.

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Although some of the symptoms are the same, the treatments for HAE and histamine-mediated angioedema are totally different, Craig says.

Histamine- or Mast Cell–Mediated Angioedema

Treatment starts with non-sedating antihistamines, Craig says.

Non-sedating histamines include:

• cetirizine (Zyrtec)
• desloratadine (Clarinex)
• fexofenadine (Allegra)
• loratadine (Claritin)

If antihistamines alone don’t control the symptoms, your doctor may prescribe:

• cyclosporine
• dupilumab (Dupixent)
• omalizumab (Xolair)
• prednisone or prednisolone, which are corticosteroids
• remibrutinib (Rhapsido)

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Hereditary Angioedema (HAE)

HAE treatment targets the bradykinin pathway, not histamine; allergy medications don’t help. Drug therapy for HAE includes both on-demand and preventive medications.

On-demand (acute) treatments are used to stop an HAE attack once it begins. Experts recommend that everyone with HAE should have access to one of these medications, which include:

• C1 esterase inhibitors (C1-INH): Berinert and Ruconest, both of which are subcutaneous injections
• Kallikrein inhibitor: sebetralstat (Ekterly), taken as an oral tablet
• Bradykinin B2-receptor antagonists: ecallantide (Kalbitor) and icatibant (Firazyr), both subcutaneous injections

Preventive (prophylactic) treatments are taken regularly to help reduce the frequency and severity of HAE attacks. These medications include:

• C1 esterase inhibitors (C1-INH): Cinryze, taken intravenously, and Haegarda, a subcutaneous injection
• Kallikrein inhibitors: berotralstat (Orladeyo), an oral tablet, and lanadelumab (Takhzyro), a subcutaneous injection
• Activated factor 12a (F12a) inhibitor: garadacimab (Andembry), a subcutaneous injection

Talk to your healthcare provider if you have repeated bouts of swelling, especially if you don’t know what caused them.

“If you have a case of angioedema, you should get in touch with your doctor, especially because swelling can involve the airway in both hereditary and histamine-induced forms,” says Craig.

Get emergency care immediately if you have:

• Swelling of your tongue, lips, or throat
• Trouble breathing or swallowing
• Severe abdominal pain, severe vomiting, or diarrhea

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• Both hereditary and allergic angioedema cause swelling, but their root causes and treatments are very different.
• Allergic or histamine-mediated angioedema often improves with antihistamines or other allergy medications.
• Hereditary angioedema (HAE) is a genetic condition that requires specialized medications that target the bradykinin pathway.
• Because swelling in either type can block the airway, seek emergency care immediately if you have trouble breathing or swallowing.