Most types of hereditary angioedema (HAE) happen when a protein called C1 inhibitor (C1INH) is too low or doesn’t work well. But what if a blood test for HAE shows that your C1INH is normal? Could you still have HAE?

HAE with normal C1 inhibitor (HAE-nC1INH), formerly called type 3 HAE, is the rarest and most recently discovered type of HAE. Although people with HAE-nC1INH have normal C1INH levels and function, the condition can cause many of the same swelling symptoms as other types of HAE.

Unlike other types of HAE, HAE-nC1INH doesn’t show up on standard blood tests, which can make it more difficult to diagnose. Learning more about this rare form of HAE can help you better understand the condition and what to expect. This article discusses 11 facts about HAE-nC1INH, including symptoms, triggers, testing, and treatment options to discuss with your doctor.

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Most cases of HAE are diagnosed during childhood, with symptoms appearing by age 13 and increasing during puberty. HAE-nC1INH is usually diagnosed later, with symptoms first appearing between ages 20 and 26.

Doctors often use C1INH blood tests to diagnose HAE. One test, called a C1INH quantitative test, measures the amount of C1INH in the blood and can help diagnose type 1 HAE. Another test, called a C1INH functional test, measures how well C1INH works and can help diagnose type 2 HAE.

There isn’t a blood test that diagnoses HAE-nC1INH because C1INH levels and function are normal. This can make HAE-nC1INH more difficult to diagnose than other types.

Changes in the hormone estrogen, including the use of estrogen-containing birth control, are a well-known trigger for HAE attacks. People with HAE-nC1INH are often more sensitive to estrogen than people with other types of HAE. Some people have attacks only when they’re exposed to estrogen.

Because of this strong link to estrogen, researchers once believed that HAE-nC1INH affected only women, according to the journal Clinical Reviews in Allergy & Immunology. They now know this type is more common in women, but anyone can develop it.

Your doctor may recommend avoiding or stopping medications containing estrogen if you have HAE-nC1INH. For example, they may suggest a progestin-only birth control method to help reduce the risk of HAE attacks.

Estrogen isn’t the only trigger for attacks in HAE-nC1INH, and not all attacks have a clear trigger. Depending on the subtype, other triggers may include:

• Physical trauma, including from surgery or dental procedures
• Menstruation
• Warm weather
• Stress and anxiety
• Infections
• Certain medications, including ACE inhibitors

Swelling attacks in HAE-nC1INH are similar to those seen in other types of HAE. Common areas affected include:

• Arms
• Legs
• Face
• Tongue
• Throat

Compared with people who have types 1 and type 2 HAE, people with HAE-nC1INH are less likely to experience swelling in multiple areas at the same time. They’re also less likely to have swelling in the gastrointestinal tract, which can cause symptoms such as nausea and diarrhea. However, gastrointestinal swelling can still occur.

Some studies suggest that throat swelling may be more common in people with HAE-nC1INH than in people with type 1 or type 2 HAE. Swelling that affects the throat or airway can cause trouble breathing. This can be life-threatening and requires immediate treatment, even if you’ve already used an on-demand HAE medication to reduce swelling.

What To Do in an Emergency

If you or your child develops throat swelling during an HAE attack, call 911 or your local emergency number right away. If you have on-demand HAE medication, use it immediately according to your doctor’s instructions. Signs that an attack is affecting your throat include:

• Trouble swallowing
• Shortness of breath
• A swollen tongue

Some reports suggest that certain subtypes of HAE-nC1INH can cause hemorrhage (bleeding) under the skin either before or during an attack. The bleeding may appear as bruising or small red or purple spots. This symptom isn’t typically seen in people with type 1 and type 2 HAE.

Along with your symptoms and family history, genetic testing can help doctors diagnose HAE-nC1INH by identifying genetic mutations (variants) linked to the condition.

Some people have symptoms of HAE-nC1INH without any known disease-causing gene variants. New genetic testing techniques have identified more genes linked to HAE, which may help more people get an accurate diagnosis.

HAE-nC1INH is treated much like types 1 and 2. Although research on treating HAE-nC1INH is limited, HAE medications usually fall into two categories:

• On-demand medications — Also called rescue medications, these medications are kept on hand to use at the first sign of an HAE attack. These drugs aim to reduce the severity of an attack and help prevent life-threatening complications, especially when taken as soon as symptoms begin.
• Prophylactic (preventive) medications — Your doctor may prescribe preventive medications to reduce the frequency and severity of HAE attacks. Long-term prophylaxis involves taking medications regularly to help prevent attacks, and short-term prophylaxis involves taking preventive medication before a known trigger (such as a dental procedure).

Although studies on treating HAE-nC1INH are limited, researchers know that people can respond very differently to the same medication. A treatment that works well for someone else may not effectively treat or prevent attacks in you or your child.

A person’s response to a medication may depend on their subtype of HAE-nC1INH. Your doctor can help you find the treatment plan that works best for you.

People with HAE-nC1INH may have long periods of remission, when they don’t have swelling symptoms or attacks. The frequency of attacks varies from person to person. Some people go months or even years without symptoms, while others have frequent attacks.

Talk With Your Doctor

If you or your child has HAE-nC1INH or develops symptoms that could be HAE, talk to your doctor about testing and treatment options.

Your hereditary angioedema specialist can help you identify triggers that may cause attacks and develop a plan for managing sudden swelling and emergencies. They can also recommend preventive and on-demand treatments to help reduce the impact of HAE on your quality of life.

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On myHAEteam, people share their experiences with hereditary angioedema, get advice, and find support from others who understand.

How do you manage HAE with normal C1 inhibitor? Let others know in the comments below.