Hereditary angioedema

Synonyms

1

Overview

Hereditary angioedema is an immune disorder characterized by recurrent episodes of severe swelling. The most commonly affected areas of the body are the limbs, face, intestinal tract, and airway. HAE is caused by low levels or improper function of a protein called C1 inhibitor which affects the blood vessels. This condition is inherited in an autosomal dominant pattern.

There are three types of HAE, types I, II, and III. The types can be distinguished by their underlying causes and levels of C1 inhibitor in the blood. Type I and II are caused by mutations in the SERPING1 gene. Some cases of type III are associated with mutations in the F12 gene. Other genes are likely to be identified as the cause of other cases of HAE type III.

Symptoms

Hereditary angioedema is characterized by recurrent episodes of severe swelling (angioedema). The most commonly involved areas of the body are the limbs, face, intestinal tract, and airway. While minor trauma or stress may trigger an attack, swelling often occurs without a known trigger. Episodes involving the intestinal tract cause severe abdominal pain, nausea, and vomiting. Swelling in the airway can restrict breathing and lead to life-threatening obstruction of the airway. About one-third of people with this condition develop a non-itchy rash called erythema marginatum during an attack.

Symptoms of hereditary angioedema typically begin in childhood and worsen during puberty. Untreated individuals may have an attack every 1 to 2 weeks. Most episodes last 3 to 4 days. The frequency and duration of attacks vary greatly among individuals with hereditary angioedema, even among those in the same family.

Symptoms of hereditary angioedema may be summarized by: 

  • Swelling in the arms, legs, lips, eyes, tongue, or throat
  • Airway blockage (involves throat swelling and sudden hoarseness)
  • Repeat episodes of abdominal cramping without obvious cause
  • Intestinal swelling can be severe and include vomiting, dehydration, pain, and occasionally shock

Causes

Hereditary angioedema (HAE) is caused by low levels or improper function of the protein C1 inhibitor. This problem affects the blood vessels. There is usually a family history of the condition. However, relatives may be unaware of previous cases, which may have just been reported as an unexpected, sudden, and premature death of a parent, aunt, uncle, or grandparent.

Many attacks occur without reason. However, anxiety, stress, sickness (including colds and the flu), and surgery have been shown to trigger certain attacks of hereditary angioedema. Dental procedures increase the risk of attacks in patients with HAE.

Prevention

Treatment with ACE inhibitors is contraindicated in this condition, as these drugs can lead to bradykinin accumulation, which can precipitate disease episodes.

Long-term prophylaxis

Patients in whom episodes occur at least once a month or who are at high risk of developing laryngeal edema require long-term prophylaxis. There are now several phase III clinical trials recently published in HAE prophylaxis and therapy and these have led to the licensing of pdC1INH (Berinert®, CSL Behring; Cinryze®, ViroPharma; Cetor-n®, Sanquin) in many parts of the world; bradykinin receptor antagonist (Icatibant, Firazyr®, Jerini/Shire) in Europe; kallikrein inhibitor(Ecallantide, Kalbitor®, Dyax) in the United States; and recombinant C1-INH replacement therapy (rhC1INH; conestat alfa; Rhucin®, Pharming) in Europe. Tranexamic acid has been showed to be relatively ineffective therapy. Danazol prophylaxis remains an option but therapeutic agents are now being used more for prophylaxis because of danazol adverse events. For patients requiring long-term prophylaxis, home therapy which allows patients to self-administer product, is considered an integral part of allowing patients a normal quality of life.

Short-term prophylaxis

Short-term prophylaxis is normally administered before surgery or dental treatment. In Germany, C1-INH concentrate is used for this and given 1–1.5 hours before the procedure. In countries where C1-inhibitor concentrate is not available or only available in an emergency (laryngeal edema), high-dose androgen treatment is administered for 5–7 days.

Diagnosis

Recognizing HAE is often difficult due to the wide variability in disease expression. The course of the disease is diverse and unpredictable, even within a single patient over their lifetime. This disease may be similar in its presentation to other forms of angioedema resulting from allergies or other medical conditions, but it is significantly different in cause and treatment. When hereditary angioedema is misdiagnosed as an allergy it is most commonly treated with steroids and epinephrine, drugs that are usually ineffective.

HAE accounts for only a small fraction of all cases of angioedema. To avoid potentially fatal consequences such as upper airway obstruction and unnecessary abdominal surgery, the importance of a correct diagnosis cannot be over-emphasized.

Consider Hereditary Angioedema (HAE) if a patient presents with:

  • Recurrent angioedema (without urticaria)
  • Recurrent episodes of abdominal pain and vomiting
  • Laryngeal edema
  • Positive family history of angioedema

 A blood test, ideally taken during an episode, can be used to diagnose the condition. Measure: serum complement factor 4 (C4), C1 inhibitor (C1-INH) antigenic protein, C1 inhibitor (C1-INH) functional level if available.

Analysis of complement C1 inhibitor levels may play a role in diagnosis. C4 and C2 are complementary components

Prognosis

Hereditary angioedema can be life threatening and treatment options are limited. It is very important that patient avoid triggers, such as anxiety and trauma. How well a person does depends on the individual's specific symptoms.

Treatment

Medical treatment of hereditary angioedema (HAE) consists of preventing attacks and managing acute attacks once they occur. During attacks, patients may require respiratory support. They also may require large amounts of intravenous fluids to maintain hemodynamic stability.

Approved therapies:

  •  Ecallantide (Kalbitor) - FDA approved for the indication: Treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older
  • Icatibant (Fyrazir) -  FDA approved for the indication: Treatment of acute attacks of hereditary angioedema in adults 18 years of age and older
  •  C1 esterase inhibitor, human ( Cinryse) - FDA approved: Routine prophylaxis against angioedema attacks in patients with Hereditary Angioedema (HAE)


Resources

  • NIH
  • Genetics Home Reference