Hereditary angioedema (HAE) is a rare genetic condition that causes sudden swelling attacks. Swelling can happen in the hands, feet, face, stomach, genitals, throat, or airway.

Blood tests are one of the most important ways to diagnose HAE. Along with your symptoms and family history, blood tests help confirm your diagnosis and rule out other conditions.

It can take several years to get an HAE diagnosis, so getting the right tests is important. This article explains the blood tests used to diagnose HAE. We’ll cover what your results mean and how doctors rule out other similar conditions.

What Are the Key Laboratory Tests for HAE?

Lab tests for HAE look at complement proteins. The complement system is made of more than 50 immune system proteins. They help kill invading bacteria and infected cells to protect you from infection.

Problems with complement system proteins can lead to inflammatory conditions, like HAE. Along with your symptoms and family history, blood tests can help doctors diagnose HAE. Your doctor will look for changes in your complement protein levels and how well they work.

C4 Level Testing

One of the most important lab tests for HAE measures your levels of complement 4 (C4), a protein in the complement system. People with HAE types 1 and 2 typically have low C4 levels during an HAE attack or flare-up. People with HAE with normal C1INH, sometimes called type 3 HAE, usually have normal C4 levels.

Those with type 1 HAE can also have low C4 levels even when they’re not having an attack. Your doctor will likely recommend other HAE lab tests if your C4 protein levels are less than 50 percent of what they should be.

Studies also show that up to 10 percent of people with HAE have normal C4 levels. This means you can’t be diagnosed by looking at C4 levels alone. You’ll need additional tests to look at other complement proteins involved in HAE.

One of the most important lab tests for HAE measures your complement 4 (C4) protein levels.

C1INH Levels and Functional Testing

C1 inhibitor, or C1INH, is a protein that plays a role in HAE. Healthcare providers can use blood tests to check how much C1INH you have and how well it works.

With type 1 HAE:

• You may have a change in a gene called SERPING1. This gene tells your body how to make the C1INH protein.
• This gene change can cause the body to make too little C1INH. People with type 1 HAE usually have less than half the normal amount of this protein in their blood.

With type 2 HAE:

• The body may make enough C1INH, but the protein does not work the way it should.

C1INH tests can help doctors tell the difference between type 1 and type 2 HAE. C1INH helps control proteins that can cause swelling. When there is not enough C1INH, or when it does not work well, swelling attacks may happen more easily.

C1q Testing

C1q is another complement protein involved in inflammation. Low C1q levels are seen in people with another type of angioedema, called acquired angioedema. Acquired angioedema can happen when immune system proteins called antibodies interfere with C1INH. It can also be linked to other health conditions, such as certain autoimmune disorders or blood cell disorders.

Measuring your C1q protein levels helps tell the difference between hereditary and acquired angioedema. In HAE, you most likely have normal C1q levels.

Other Blood Tests for HAE

Some blood tests aren’t specific to HAE, but they can help rule out other conditions. HAE diagnoses can be delayed for years. Other basic blood tests help point doctors in the right direction.

White blood cells (WBCs) are part of your immune system. They are made mostly in the bone marrow and help your body respond to infections and inflammation. When you have an infection or inflammation, your WBC count may rise.

Complete Blood Count

A complete blood count (CBC) measures your blood cells, including your WBC. During an HAE attack, your WBC count doesn’t normally increase. Your WBC count can rise if abdominal symptoms, such as pain and swelling, are caused by another condition.

A CBC can also measure levels of specific immune cells. Eosinophils are immune cells that protect your body from parasites. They also play a role in allergies, or when your body overreacts to a certain substance.

A CBC can sometimes help doctors look for signs of infection, inflammation, or another condition. However, it cannot diagnose HAE on its own.

Erythrocyte Sedimentation Rate

An erythrocyte sedimentation rate test measures inflammation in the body. It’s not one of the main tests used to diagnose HAE, but a doctor may order it if they are checking for other conditions that can cause swelling or abdominal symptoms.

How Do Blood Tests Play a Role in HAE Diagnosis?

Blood tests are just one part of an HAE diagnosis. Your doctor will first review your symptoms, which can look like those of other health conditions. Your doctor will also check your medications. Certain medications, such as ACE inhibitors, can suddenly cause angioedema episodes even if you have been taking them for years.

Specific symptoms that point to HAE include:

• Swelling or angioedema without hives
• Swelling that doesn’t improve with allergy medications, such as antihistamines or corticosteroids
• Abdominal pain
• Trouble breathing because of swelling in the airway
• Symptoms that get worse with stress, illness, or injuries

If you have any of these signs or symptoms, your doctor will likely recommend blood tests for HAE. These tests help rule out allergic conditions and confirm an HAE diagnosis.

Blood Tests Help Determine the Type of HAE

Blood tests can help doctors tell the difference between some types of HAE:

• Type 1 HAE — Low C4 and C1INH levels, and normal C1q levels
• Type 2 HAE — Low C4 levels, normal C1INH levels but low function, and normal C1q levels
• HAE with normal C1INH — Usually normal C4 and C1INH levels, normal C1INH function, and normal C1q levels

HAE with normal C1INH can be harder to diagnose because complement test results are usually normal. Doctors may use symptoms, family history, and sometimes genetic testing to help confirm this type.

Low C1q levels are more often linked to acquired angioedema, not HAE with normal C1INH.

A Single Blood Test Can’t Diagnose HAE

There is no single test that can diagnose HAE. C1INH level testing alone is not enough to diagnose or rule out HAE. Some people with type 2 HAE have normal or high C1INH levels, but the protein does not work as it should.

This is why doctors usually order C4 testing, C1INH level testing, and C1INH function testing together. They may also repeat abnormal tests to confirm the diagnosis. Results can sometimes be affected by timing, how the blood sample is handled, age, pregnancy, or normal test variation.

HAE is usually an inherited genetic disorder. This means it can be passed down from parents to their children. You may also have genetic testing done in addition to the other blood tests. Genetic testing may help diagnose HAE if you have normal C1INH levels.

Join the Conversation

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

Which blood tests did you get when you received an HAE diagnosis? Let others know in the comments below.