Hereditary angioedema (HAE) is a rare genetic condition that causes swelling attacks. Most people with HAE will inherit the condition from a parent, and many first experience symptoms between the ages of 2 and 20. HAE affects about 1 in every 50,000 people and is grouped into three main types.

Below, we’ll discuss the three types of HAE and how they differ from one another.

Symptoms of HAE

HAE attacks can vary from mild to severe. Episodes usually last between two and five days.

Depending on which part of the body is affected, swelling may lead to various symptoms, such as:

• Swollen skin on the face, feet, hands, or genitals
• Diarrhea
• Nausea with or without vomiting
• Abdominal pain or cramping due to swelling in the gastrointestinal (GI) tract, also called the digestive tract
• Swollen tongue
• Trouble swallowing or talking
• Noisy breathing
• Difficulty breathing due to throat or airway swelling

HAE Triggers

HAE episodes often seem to occur randomly. Some people may experience warning symptoms prior to swelling attacks, such as erythema marginatum (a flat, blotchy rash that usually doesn’t itch).

Although what brings on HAE attacks can vary, episodes may be triggered by:

• Injuries
• Surgical or dental procedures
• Certain medications, such as angiotensin-converting enzyme (ACE) inhibitors
• Emotional stress or anxiety
• Illnesses like colds
• Repetitive activities like computer typing or shoveling

Although the three types of HAE share similarities, there are important differences that separate them. These differences influence how each type is diagnosed and managed.

🗳️ Do you know which type of hereditary angioedema (HAE) you have?

Yes, type 1

Yes, type 2

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About 85 percent of people diagnosed with HAE have type 1. This type is caused by low levels of C1INH. Type 1 HAE is also classified as C1INH deficiency.

The C1INH protein helps regulate immune and blood pathways involved in inflammation and fluid leakage. Low levels of this protein can lead to a buildup of an inflammatory peptide called bradykinin, a substance that makes blood vessels leak fluid into nearby tissues. Swelling attacks happen when these leaked fluids build up in nearby tissues.

Doctors use blood tests to diagnose HAE. In type 1, blood test results will often show low levels of C1INH and complement component 4 (C4) proteins, as well as low C1INH function. Having a low C1INH protein level, specifically, supports a diagnosis of type 1 HAE. Low C4 levels, especially during an HAE attack, can also support the diagnosis.

Genetic testing for SERPING1 gene mutations, a physical exam, and a detailed medical history may also be used to help support an HAE diagnosis.

Type 2 HAE accounts for around 15 percent of all cases. It is also considered a type of C1INH problem. However, this name can be confusing because people with type 2 HAE usually make normal or higher-than-normal amounts of C1INH protein.

In these cases, C1INH deficiency comes from the fact that the protein doesn’t work properly. Like those with type 1 HAE, people with type 2 carry a mutation in their SERPING1 gene. But instead of causing low C1INH levels, these variants cause the body to make C1INH protein that doesn’t function normally.

This type is also diagnosed using blood tests, genetic testing, a physical exam, and a detailed history. Blood test results indicative of type 2 HAE include:

• Normal or elevated levels of C1INH
• Low C1INH function
• Low levels of C4

Type 2 HAE can lead to higher than normal C1INH levels. One small study found that 77 percent of people with type 2 HAE had higher-than-normal levels of C1INH protein, compared with 39 percent of people without HAE.

Scientists suggest this may happen because the faulty C1INH protein in type 2 HAE can’t be cleared from the blood as usual, causing it to build up.

HAE with normal C1 inhibitor — formerly called HAE type 3 — is the rarest of the three main types. In fact, health experts don’t know exactly how many people have HAE-nC1INH, just that it’s quite rare. In this type of HAE, C1 inhibitor occurs at normal levels and is able to work normally.

While type 1 HAE and type 2 HAE are linked to variants in the SERPING1 gene, HAE-nC1INH can involve changes in several different genes. These may include PLG, ANGPT1, KNG1, MYOF, HS3ST6, CPN1, DAB2IP, and F12.

Some forms of HAE-nC1INH — including those linked to changes in the F12 and PLG genes — appear to cause swelling by increasing the activity of bradykinin.

Other forms seem to work through a different pathway involving a protein called vascular endothelial growth factor (VEGF), a protein involved in blood vessel function. Researchers are still learning how these pathways cause swelling.

Diagnosing HAE-nC1INH can be challenging. This is because blood tests often reveal normal levels of C1 inhibitor and function. Blood tests can be used to rule out other causes of swelling.

Genetic testing may be used to identify mutations linked to the condition, but not all genetic causes are known. Because of this, diagnosis often relies on:

• Symptoms
• Family history
• Absence of C1INH deficiency and exclusion of other causes of swelling
• Response to bradykinin-targeted treatments

HAE-nC1INH is sometimes referred to as estrogen-dependent or estrogen-associated HAE. This type is more common in females, according to research in Clinical Reviews in Allergy & Immunology, and research suggests it may be more strongly influenced by estrogen levels.

Hormone-related triggers that may prompt swelling episodes include:

• Puberty
• Menstrual cycle hormonal changes, such as menstruation (periods) and ovulation (the release of an egg from an ovary)
• Pregnancy
• Menopause
• Hormonal birth control pills containing estrogen
• Hormone replacement therapies
• Other changes in estrogen levels

It’s important to note that hormonal factors may also be triggers for people with C1INH deficiency (type 1 HAE and type 2 HAE). Compared with people who have C1INH deficiency, people with HAE-nC1INH appear more likely to experience swelling of the face, tongue, and throat and less likely to have GI swelling and abdominal pain.

How HAE Type Affects Treatment

There are two types of treatments for HAE:

• On-demand (rescue) medications treat HAE attacks as they’re happening. Taken at the first sign of an attack, these help reduce symptom severity and the risk of complications.
• Prophylactic (preventive) medications prevent future attacks or reduce how often they happen.

On-Demand Medication

On-demand treatment depends on your type of HAE. This may begin reducing symptoms within about 30 minutes to two hours, depending on the treatment and the attack. Some rescue medications replace C1INH or help it work, while others block kallikrein or bradykinin, substances involved in HAE swelling.

Types of on-demand treatments for HAE include:

• C1 inhibitor replacement therapies
• Kallikrein inhibitors, such as ecallantide and sebetralstat
• Bradykinin B2 receptor blockers, such as icatibant

Icatibant and C1 inhibitor therapies have helped treat most attacks in people with HAE-nC1INH caused by F12 gene changes, but responses can vary. Similar treatments have also helped some people with HAE-nC1INH caused by PLG gene changes.

No matter the HAE type, signs of throat and airway swelling should be treated as a life-threatening emergency. Seek immediate medical care if you experience swelling of the tongue or throat or difficulty breathing or swallowing, even if you’ve taken rescue medication.

Preventing HAE Attacks

Some medications are taken regularly to reduce the frequency and severity of future HAE attacks. For people with type 1 and 2 HAE, these may include:

• Preventive C1 inhibitor therapy
• Kallikrein inhibitors, such as lanadelumab and berotralstat
• Hormonal therapy, such as androgens and progestins
• Antifibrinolytics, such as tranexamic acid

For people with HAE-nC1INH, treatment may depend on the gene change involved. For example, long-term preventive treatments — including tranexamic acid, androgens, progestins, and lanadelumab — may help people with an F12 gene change, while tranexamic acid and androgens have helped most people with a PLG gene change.

There is very little evidence on short-term prevention for HAE-nC1INH. Short-term prevention means taking medication before a known trigger, such as surgery. For people with HAE linked to F12 gene changes, preventive C1 inhibitor therapy has been reported to help prevent attacks.

HAE can look different from person to person, but knowing your type can help you and your doctor make a treatment plan that fits your needs. If you have swelling attacks or a family history of HAE, talk with a doctor about testing and treatment options.

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