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Understanding hereditary angioedema (HAE)

Understanding hereditary angioedema (HAE)

What is HAE?

Hereditary angioedema (HAE) is a rare, inherited (meaning it can be passed from parent to child) condition that causes episodes (also known as ‘attacks’, or ‘acute attacks’) of considerable swelling in various parts of the body.

HAE occurs equally in men and women and, as an inherited disorder, it is a lifelong condition.
The word ‘angioedema’ in hereditary angioedema is the name for the type of swelling (or ‘oedema’) that occurs in HAE. Specifically, angioedema is a type of swelling caused by an accumulation of an excessive amount of watery fluid in cells, tissues or abdominal cavities. The swelling of HAE may also be referred to by doctors as ‘non-pitting oedema’, because if you press on the area the skin bounces back and does not leave an indentation, or ‘pit’.

Depending on the individual and the severity of their disease, some people will have many swelling attacks each month, while others will go months or even years without one.

In HAE, swelling can occur almost anywhere, but it is most likely to be found in one of the following body parts:

As well as occurring in different body parts during different attacks, the swelling of HAE can move from one site to another during a single attack. For example, a facial attack may move to the throat. Doctors refer to these as ‘migratory attacks’, and these travelling attacks tend to last several days longer than attacks of oedema that affect only one site. HAE attacks can be debilitating – for example, swelling of the intestines can sometimes cause severe abdominal pain. The most serious type of attacks, however, are those of the voice box, or larynx – referred to as laryngeal attacks. These can cut off the air supply to the lungs, making it difficult to breathe, and may be life-threatening. This type of attack is a medical emergency requiring immediate assistance.

Attacks that affect the arms, legs, hands, feet or genitals are called ‘peripheral attacks’. These can cause painful swelling and may prevent everyday activities. Despite their impact on day-to-day functioning, peripheral attacks can often be underestimated.

Recognising the symptoms of HAE

The symptoms of HAE are similar to those of some other types of medical conditions, particularly allergic reactions. However, there are some clues that help doctors distinguish the symptoms of this rare disease from those caused by allergy.

Swelling on one side of the body – indicates HAE

Swelling on one side of the body – indicates HAE

In allergic reactions, both sides of the body are likely to be affected, whereas HAE attacks may involve just one side of the body, for example, the right hand but not the left, or vice versa.

Irritated eyes – indicates allergy

Irritated eyes – indicates allergy

In allergic reactions, the eyes tend to be watery and itchy. Although people with HAE may also have allergies, itchy, watery eyes are not a symptom of an HAE attack.

Response to anti-allergy treatments – indicates allergy

Response to anti-allergy treatments – indicates allergy

Allergic reactions to foods, medicines, or insect bites tend to respond quickly to treatments such as adrenaline (epinephrine), antihistamines, and corticosteroids. HAE attacks spontaneously improve over time, and it may even initially appear that anti-allergy drugs are effective in HAE attacks. However, whereas an allergic reaction will respond quickly and dramatically to an anti-allergy treatment, an HAE attack will not show such dramatic improvement.

Eight simple questions: symptoms of HAE?

Answer these questions to see if your symptoms fit the profile of HAE:

1

Have you had unexplained attacks of swelling in your hands, feet, arms, legs, face, throat, or genitals?

2

Have these swelling attacks occurred on just one side of your body, for example, just your left hand or just your right foot?

3

Have you had unexplained attacks of abdominal pain?

4

Have these attacks of swelling or abdominal pain occurred more than once?

5

Has anyone in your family had similar episodes of swelling or abdominal pain?

6

Do you sometimes feel warning signs (such as fatigue, tingling, nausea, or flu-like symptoms) that an attack will begin — minutes, hours, or even days before an attack?

7

Have prescription medications, such as antihistamines, adrenaline (e.g., EpiPen^®) or steroid injections provided little relief, if any?

8

When you’ve had these attacks, have your eyes been watery or itchy?

If you answered “yes” to all or nearly all of the first seven questions and “no” to the last question, your symptoms may suggest HAE. You should discuss your medical history with your GP who will be able to assess your symptoms, conduct some investigations and decide whether you need to be referred to an immune system specialist, called an immunologist, who can help further with diagnosis and treatment.

What causes HAE?

HAE is a hereditary condition, which means that most (but not all) of the people who have it inherit it from one of their parents. So, although it is possible to be the first person in your family to have HAE, in most cases other family members have also had similar swelling attacks.

The swelling of HAE is most commonly caused by the poor functioning or lack of a protein called C1 esterase inhibitor (C1-INH). C1-INH is part of the immune system — the system of the body that recognises and attacks foreign invaders, such as viruses or bacteria.

C1-INH is involved in many different reactions in the immune system. Without adequate amounts or correct functioning of C1-INH, blood vessels can become leaky, allowing fluid to build up in the tissue, causing the swelling that is characteristic of HAE.

There are three main types of HAE:

Type I

Type I

Overall levels of C1-INH are low in people with type I HAE. About 85% of people with HAE have type I, making it the most common type.

Type II

Type II

In type II HAE, levels of C1-INH are normal, but the C1-INH that is in the body does not function properly. About 15% of people with HAE have type II, making it the second most common type of HAE.

Type III

Type III

This is a very rare form of HAE which has only recently been recognised by doctors. It mainly affects females and is made worse by high levels of oestrogen, which may occur as the result of taking oral contraceptives, or pregnancy. Type III HAE is not due to C1-INH deficiency; C1-INH lab tests are normal, but the patient has symptoms of HAE. The exact cause of type III is not clearly defined.

To understand how HAE is inherited, it’s helpful to look at genetics. People receive half their genetic code from their mother and half from their father. The genetic code is carried in units called ‘genes’.

In some diseases, such as cystic fibrosis or sickle-cell anaemia, a child will only get the disease if they receive an abnormal, disease-causing gene from each of their parents. This type of gene, that usually only causes a disease when a person has two copies, is called a ‘recessive’ gene. This means that although the parents of the affected child each have an abnormal gene, they may not have the disease themselves. These parents are considered ‘carriers’ of the disease.

In HAE, having just one abnormal gene will cause the disease. Biologists call these types of genes ‘dominant’. This means that there is a 50/50 chance that a child who has one parent with HAE will also have HAE themselves.

Children born without the abnormal gene will effectively put an end to the occurrence of HAE in that branch of the family tree. All following generations (that child’s children and grandchildren etc.) will be free of HAE.

Occasionally, HAE can occur in a person without a previous family history of HAE. This is due to a spontaneous change in the genetic code for the C1-INH protein, creating an abnormal version of the gene. Not only will this person have the disease, but he or she will also have the potential to pass on this changed gene (and therefore the disease) to his or her children.

How is HAE diagnosed?

Type I and type II HAE can be diagnosed with a blood test that will usually be carried out if a doctor suspects that a person may have HAE.

The blood test measures the level of C1-INH in the blood, and how well the C1-INH is functioning. The test may also look for another important blood protein called C4, which is sometimes low in people with either type I or type II HAE.

A diagnosis of type I HAE will be confirmed if a low level of C1-INH is found. People with type II HAE will have a normal C1-INH level, but the C1-INH that is found in their blood will not be functioning properly. No single test can diagnose type III HAE.

Other types of angioedema

As well as hereditary angioedema, there is also a type of angioedema that is not inherited.

Acquired (i.e. non-hereditary) angioedema

This is usually caused by the body developing molecules that stop C1-INH from working properly. These molecules are called antibodies. This type of angioedema may occur in people who have cancer of the lymphatic system or those with an autoimmune disease (where the body responds to normal body proteins as if they were dangerous bacteria or viruses and begins to attack them).

As a non-hereditary condition, this type of angioedema is not passed on from parent to child.

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