Understanding Hereditary Angioedema: Causes, Symptoms, and Management

Transient but often pronounced episodes of swelling, primarily of the face but also of the hands, feet, or airways: such symptoms indicate angioedema. This usually occurs as part of an allergic reaction and is rarely the result of a congenital disorder. Then, however, additional gastrointestinal complaints typically happen. The swellings are caused by accumulations of water (oedema) in the subcutaneous tissue; Angioedema on the face used to be known as Quincke’s oedema.

Angioedema: what forms are there?

First of all, two forms of angioedema must be distinguished, as these two require different treatments in principle:

• Angioedema is caused by the messenger substance histamine ( histamine-mediated angioedema ), which is released to a greater extent in an allergy or an intolerance reaction to medication, for example. This mechanism is similar to that which occurs in hives (urticaria).
• Much more rarely, the insufficient function of a specific molecule is the basis – the C1 inhibitor ( angioedema due to C1 inhibitor deficiency  – in short, AAE), which generally slows down the immune system in uncontrolled reactions. This form is usually inherited and, therefore, congenital ( hereditary angioedema – in short, HAE). The acquired forms of this C1 inhibitor deficiency develop either in the context of cancers of the lymphatic system or as a result of autoimmune diseases.

 

What are the causes of hereditary angioedema?

In patients with hereditary angioedema, a protein called C1 esterase inhibitor is reduced in the blood plasma. This protein inhibits the first component of the complement system. The complement system, in turn, consists of a cascade of serum proteins that play essential roles in the human body’s immune and inflammatory response.

This disorder is inherited – if one parent is affected, there is a 50 per cent chance that a child will inherit the condition.

Who is affected and why?

The age at onset of HAE symptoms varies greatly, but there is a frequency peak in the first decade and a second in the second decade of life. About 75 per cent of patients are symptomatic by the age of 20. Attacks seem to occur more frequently during adolescence and early adulthood. For example, taking the contraceptive pill is reported as the trigger for the first HAE attack in previously normal patients.

Another triggering factor can be an infection, such as the uncommon viral infection mononucleosis (glandular fever).

The attacks can also occur without recognizable external causes; stress, fear or minor injuries can provoke them. Dental treatment, for example, can contribute to swelling of the mucous membranes in the airways. In addition, other triggers (e.g., hand swelling after lawn mowing, writing, hammering, etc.) have been described.

 

Frequency of hereditary angioedema

The frequency of HAE attacks varies enormously. Some patients are symptom-free for a long time, then swelling occurs at short intervals. Other sufferers experience attacks at faster, more regular intervals.

Hereditary angioedema: Symptoms

The typical symptoms of HAE disease are the transient occurrence of painful, non-itching swellings that are colourless and lie in the subcutaneous tissue or acute abdominal pain with no other apparent cause.

Patients often report a feeling of tightness at the site where the oedema occurs about 30 minutes to a few hours later. The swelling lasts at least four hours – on average between 24 and 72 hours – but it can last longer in individual cases.

Hereditary angioedema during menstruation and pregnancy

In women, menstruation and pregnancy appear to affect disease activity. Some women report an increase in the number of attacks during their menstrual period.

During pregnancy, some patients report an increase, and others say a decreased frequency of attacks.

The use of oral contraceptives (birth control pills, especially those with a high estrogen content) or hormone-containing intrauterine devices appears to increase the frequency and severity of mucosal swelling.

 

Hereditary Angioedema: Diagnosis

The clinical suspicion is confirmed by measuring the C1 esterase inhibitor activity or the C1 esterase inhibitor antigen in the blood plasma.

Treatment for HAE

There is currently no cure for patients suffering from HAE attacks. No therapy to date can completely prevent the attacks. Nevertheless, the symptoms can be relieved, and the progression of the oedema can be prevented. There are three types of therapy: long-term prophylaxis, short-term prevention and the treatment of acute attacks.

Who needs long-term prophylaxis?

Not all patients with hereditary angioedema require long-term prevention, but only those who have one or more of the following:

• the swelling of the mucous membrane affects the respiratory tract
• the attacks occur more than once a month
• the attacks or the illness is so severe that the patient can no longer take part in everyday life

 

First-line treatment option for hereditary angioedema

The administration of C1 esterase inhibitor concentrate has proven highly effective in long-term prevention and acute therapy – especially in patients with side effects to the androgens previously used. The intravenous administration supplies the missing enzyme to the patient directly. Severe undesirable side effects are not yet known.

Other Treatment Options: Androgens

Androgens were used before C1 esterase inhibitor concentrate was the drug of choice. However, the repeated occurrence of benign liver tumours under the androgen danazol led to the substance being taken off the market in Germany in 2005.

Androgens are male sex hormones with two properties: They increase protein production in the human organism and influence the development of male sex characteristics (e.g. increased hair growth, deeper voice).

Androgens and their effects on the organism

Androgens have been used successfully in the treatment of HAE at doses ranging from 50 to 200 mg/day but can lead to virilization (“masculinization”) in women. In addition, they can cause irregularities in the menstrual cycle, weight gain, mood changes, and negatively affect liver function.

While androgens such as danazol can be obtained from international pharmacies, it is advisable to initiate such treatment under supervision at an HAE treatment centre. The use of androgens is contraindicated in children, as well as in pregnancy and in women who want to have children.

 

Short-term prophylaxis and therapy of acute attacks of HAE

Short-term prevention is essential when patients with hereditary angioedema require surgery or dental treatment. In this case, the missing enzyme C1 esterase inhibitor can be administered as an intravenous or infusion. The needed dose is usually 500 to 1000 units of C1 esterase inhibitor concentrate.

In acute cases, the missing substance C1 esterase inhibitor concentrate is immediately administered intravenously. This brings about a rapid termination of the attack and regression of the mucosal oedema. An acute HAE attack is unresponsive to standard therapy for histamine-mediated angioedema.

Complications of hereditary angioedema

The seizures are particularly dangerous when they occur in the respiratory tract. In this case, the mucous membrane can block the airway and make it necessary to perform an emergency tracheotomy (windpipe incision). Untreated swelling of the mucous membrane in the trachea is one of the leading causes of death in HAE patients.

If the HAE was not previously recognized, a mortality of 25 to 30 per cent of the patients has been observed in the past. Therefore, in the event of swelling of the mucous membrane in the larynx area, immediate administration of C1 esterase inhibitor concentrate and medical treatment is necessary.