Hereditary angioedema

What is hereditary angioedema?

Hereditary angioedema (HAE) is a rare disease. The word “hereditary” means “inherited”. Typical symptoms of HAE are fluid retention and swelling (edema) of the subcutaneous tissue. They occur in attacks, can last for several days and then subside spontaneously.

The edema can affect different parts of the body. They usually appear on the face, hands, arms, legs and feet or in the gastrointestinal tract. The swellings rarely affect the larynx, but then it becomes life-threatening, as the edema can lead to breathing difficulties and suffocation. This is a common cause of death in people with HAE.

HAE – Types

Doctors are familiar with several forms of HAE:

• HAE type I: The liver produces too little C1 inhibitor and those affected have a deficiency in their blood. At around 85 percent, this is the most common type.
• HAE type II: Although the C1 inhibitor is present in sufficient quantities in the blood, it is not sufficiently functional. HAE type II is responsible for around 15 percent of cases.
• HAE type III: This type is extremely rare and affects other genes. The amount and function of the C1 inhibitor are normal here. Almost only women fall ill.

Hereditary angioedema – frequency and age

The frequency of hereditary angioedema is not exactly known. However, it is a rare disease. Experts estimate that 1 in 50,000 people worldwide are affected by HAE. In Europe, an estimated 10,000 to 50,000 people live with this disease; in Switzerland, it is estimated that around 160 people are affected.

As HAE is a very rare disease, the diagnosis is often made late and some sufferers are initially given a different diagnosis.

The first swelling attacks usually appear in the first or second decade of life, sometimes even later. But babies and toddlers can also develop signs of HAE. On average, the disease begins around the age of eleven. Boys, girls, men and women fall ill about equally often.

Hereditary angioedema: causes and triggers

The cause of hereditary angioedema is a genetic defect on chromosome 11, where a gene is altered (mutated) that is responsible for the production of the protein C1 inhibitor. Among other things, this inhibitor ensures that the body does not produce excessive amounts of bradykinin. This small protein (peptide) is involved in the regulation of blood pressure and increases the permeability of blood vessels.

HAE occurs when the protein C1-INH is produced in insufficient quantities (HAE type I) or does not function well (HAE type II), too much bradykinin is produced. The consequence of both types of HAE is that the blood vessels become more permeable to the blood fluid. It escapes from the blood vessels, is deposited in the tissue and triggers the attack-like swelling.

Inheritance in hereditary angioedema

The inheritance of hereditary angioedema is autosomal dominant. This means that if one parent carries the altered gene, the offspring has a 50 percent chance of also developing hereditary angioedema. The female sex is affected just as often as the male. Both the father and the mother can pass on the altered gene to their children. HEA therefore usually affects several family members.

However, there is not always a family history: in around 20 percent of those affected, the gene changes spontaneously without anyone in the family having previously suffered from hereditary angioedema. Doctors refer to this as a “new mutation”.

Hereditary angioedema – there are several triggers

The swelling attacks are usually unpredictable and no triggers can be identified. However, some “triggers” can favor them:

• Mechanical triggers such as bumps or pressure, dental surgery, removal of the tonsils, intubation
• Infections, such as a cold
• Psychological stress (positive or negative), for example in everyday life, at work and in the family
• Hormonal changes in women, such as menstruation or ovulation
• Some medications, e.g. ACE inhibitors (for high blood pressure) or hormonal contraceptives that contain oestrogens

Symptoms: Hereditary angioedema means swelling

The first symptoms of hereditary angioedema do not usually appear immediately after birth, but within the first ten years of life – or even later. The most important signs are swellings that occur in attacks.

The symptoms of HAE depend on the regions of the body in which the fluid accumulates in the tissue.

Hereditary angioedema – the harbingers of an attack

With HAE – as with migraine – there are a few signs (prodromes) that indicate an imminent swelling attack. These include, for example:

• Tiredness, fatigue
• Irritability, aggressiveness
• Depressive moods
• Tingling and tight skin
• reddish skin changes

HAE: skin swelling as symptoms

The swellings usually feel firm and appear pale or skin-colored. Most people experience a feeling of tightness, sometimes pain or a burning sensation, but no itching. Pronounced swelling can be very painful. They usually last for one to three days and then disappear again. This period can be shorter (a few hours) or significantly longer (a week).

HAE: Symptoms in the gastrointestinal tract

In addition to the skin, the walls of the digestive tract can also swell. The following symptoms then appear:

• Abdominal pain and severe abdominal cramps
• Nausea, nausea and vomiting

Other symptoms may develop as the disease progresses:

• Accumulation of water in the abdomen (ascites)
• Watery diarrhea
• Significant loss of fluids – sometimes to the point of circulatory shock

The attack can last from two to seven days. Those affected usually feel so bad that they have to stay in bed during this time. The symptoms in the digestive tract can also occur without the skin being involved.

HAE: symptoms in the airways

It can become life-threatening if the edema forms in the area of the larynx, although this is rarely the case. Those affected experience shortness of breath due to the swelling of the larynx and can suffocate. Early treatment of HAE is crucial here, and doctors must act immediately to clear the airways and ensure oxygen supply.

Hereditary angioedema: diagnosis with us

The diagnosis of “hereditary angioedema” is not easy to make. This is because the clinical picture is rare in the doctor’s office. Many doctors hardly ever come into contact with those affected and therefore have little experience with the disease. As a result, many sufferers are only diagnosed at a late stage, when they have already visited several different doctors or undergone therapies that have not brought any improvement.

Diagnosing HAE using a blood test

The diagnosis of “hereditary angioedema” can be made on the basis of a blood test. In the process

• the concentration and activity of the C1 inhibitor (C1-INH) and
• the amount of complement factor C4 – a protein in the blood plasma that plays an important role in immune defense and is part of the so-called complement system – is measured.

We can see this from the blood test:

• In HAE type I, the C1-INH values are too low. The amount and activity are less than 50 percent of normal values. C4 is also reduced in most cases.
• The situation is different in HAE type II: here the activity of C1-INH and C4 is too low, while the concentration of C1-INH is normal or even increased.

However, it only makes sense to determine these blood values after the first year of life, because only then are they meaningful enough. Sometimes all three values are within the normal range, but swellings still form in attacks. Then it could be an HAE type III.

Detecting hereditary angioedema using a genetic test

If the laboratory results are contradictory, genetic testing can be carried out as a further option for diagnosing hereditary angioedema. The genetic test for HAE type I and II can detect the altered genetic make-up on chromosome 11 in the SERPING1 gene. If HAE type III is suspected, mutations in the factor XII, angiopoietin-1 or plasminogen genes can be searched for. If the diagnosis of HAE is confirmed, all other family members should also undergo genetic testing. This enables doctors to treat the disease in good time.

Hereditary angioedema: course and prognosis

The course and prognosis of hereditary angioedema cannot be predicted in general, but vary from person to person. However, HAE is a chronic disease which, according to current knowledge, cannot be cured – and is therefore a lifelong companion. The course of the disease is often more severe in women than in men.

The swelling attacks on the skin, mucous membranes or in the gastrointestinal tract are usually easy to treat. With adequate treatment, the risk of complications can be reduced and those affected can usually lead a normal everyday life.

Hereditary angioedema: treatment

Although hereditary angioedema is easily treatable, it is not yet curable. Always look for a doctor who has experience with the treatment. There are also specialized HAE centers in Switzerland.

The therapy aims to reduce the frequency and severity of swelling attacks, prevent complications and maintain quality of life.

Prevent HAE attacks: avoid triggers

Known triggers for HAE attacks such as psychological stress, infections, estrogen-containing contraceptives or antihypertensive drugs (ACE inhibitors) should be avoided.

Doctors differentiate between the treatment of an acute swelling attack (on-demand therapy) and long-term prophylaxis, in which the number of swelling attacks is reduced by taking long-term medication.