Hereditary Angioedema (HAE)

Hereditary Angioedema (HAE) is rare, but potentially life-threatening illness that causes sudden swelling (edema) of the hands, feet, face, abdomen and airway. HAE affects about 6,000 to 10,000 individuals in the U.S.

Swelling of the airway can make breathing difficult and lead to a medical emergency. People with hereditary angioedema should seek emergency medical treatment immediately upon signs of throat swelling, difficulty breathing or other early symptoms of an attack such as tingling. Self-injectable epinephrine may be necessary to keep the airway open while awaiting emergency personnel.

Symptoms of Hereditary Angioedema

The swelling due to an attack of herediatry angioedeam usually lasts 2-5 days. The frequency, duration and and severity of angioedema attacks varies from person to person.

About 1/2 of those with hereditary angioedema will have more than one attack per month if it is left untreated, according to a survey by the U.S. Hereditary Angioedema Association.

Symptoms of hereditary angioedema usually start occurring in childhood and tend to become more severe in late childhood or adolescence.

  • Airway swelling: Edema of the larynx (voicebox) and trachea can make it difficult to breathe. Maximal swelling of the airways follows, on average, about 8 hours after the initial onset of symptoms, but difficulty breathing can develop very quickly.
  • Hands and feet: Swelling involving the feet and hands is uncomfortable and can be extremely painful. The pain may prevent some peeopl from being able to participate in normal daily activities.
  • Abdominal swelling: Swelling of the abdomen can cause severe abdominal pain, nausea, vomiting, and diarrhea. (Abdominal pain is rarely seen in other types of angioedema). The shift of fluid into the abdomen can lead to low blood pressure and shock. People with hereditary angioedema may experience many bouts of abdominal pain in the lifetimes, and even exploratory surgeries, before the source of the pain is properly diagnosed.
  • About 1/4 of people with hereditary angioedema experience a non-itching red rash that often occurs just before the attack. People with hives (urticaria) may also experience angioedema (tissue swelling), but this rash is extremely itchy and usually responds to treatment with antihistamines. Hereditary angioedema does not respond to antihistamines.

Cause of Hereditary Angiodema (HAE)

Hereditary Angioedema is due to low levels or poor function of a protein called C1 inhibitor.

The C1 inhibitor protein is part of the immune system called the complement system. The complement system includes a variety of protein (C1-C9) that work together to fight infections. C1 inhibitor helps keep the complement system under control. If the C1 inhibitor is not present, or does not work properly, the complement system can overreact. This leads to excessive swelling.

Genetics of Hereditary Angioedema (HAE)

The problems with the C1 inhibitor protein are due to changes (mutations) on a gene that control the protein. This genetic change is passed down through families.

A child has a 50% chance of inheriting HAE if one of his or her parents has the disease. Families usually know if a relative has hereditary angiodedema and can be prepared to watch for symptoms in their child. However, people may not always know their family's medical history and some relatives may not have been properly diagnosed.

Some cases of HAE are due to a spontaneous genetic change, meaning it occured in the infant while still in the womb. This means the disease was not acquired from the child's parent. However, it can be passed along to that person's own children later in life.

Hereditary Angiodema (HAE) Attack Triggers

Most HAE attacks occur spontaneously, with no apparent reason.

However anxiety, stress, minor trauma, surgical procedures, and illnesses (colds and flu) have been shown to trigger HAE attacks. Trauma to the oral cavity during a dental procedure is particularly likely to to trigger an attack with airway swelling and constriction.

Patients have also reported swelling in extremities following typing, prolonged writing, pushing a lawn mower, hammering, shoveling, and other physical activities.

In women, menstruation and pregnancy seem to have a major effect on disease activity. Some women patients report a definite increase in the number of attacks during their menstrual periods. During pregnancy, some patients note an increase in the frequency of attacks, while others have reported a decrease. Use of oral contraceptives and hormone replacement therapy is associated with an increase in the frequency and severity of attacks.

ACE Inhibitors, a class of medications used to treat blood pressure, can increase the frequency and intensity of HAE attacks. Commonly prescribe ACE Inhibitors include captopri, benazepril, enalapril (Vasotec®), lisinopril (Prinivil®, Zestril®), ramipril (Altace®), quinapril (Accupril®) and trandolapril (Mavik®).

H. Pylori (helicobacter pylori), a type of bacteria associated with the development of stomach ulcers, can trigger abdominal attacks. Treating the h. pylori bacteria with antibiotic therapy may decrease the frequency or severity of abdominal attacks.

Diagnosis of Hereditary Angioedema (HAE)

Angioedema (swelling of the tissues) can be due to other causes, such as severe allergic reactions. Laboratory analysis of blood samples or genetic testing is required to make the diagnosis of hereditary angioedema.

Blood tests that help to confirm the diagnosis of HAE include:

  • C1-inhibitor level
  • C1-inhibitor function

Other complement levels may be checked, including C2, C3, C4 and C1q.

There are different forms of hereditary angioedema that may lead to different test results.

  • HAE Type I. This type of HAE is the most common, affecting about 85% of those with HAE. It shows low levels of C1-inhibitor. C1, C3 and C1q levels are normal, but C4 is almost always low.
  • HAE Type II. This type of HAE affects about 15% of people with HAE. It shows normal or elevated levels of C1-inhibitor, but the protein does not function properly. C1, C3 and C1q are normal, but C4 is almost always low.

Treatment of Hereditary Angioedema (HAE)

Antihistamines and corticosteroids that can effectively treat allergies and hives (urticaria) are not effective for treating hereditary angioedema.

Historically, the only treatments for HAE were anabolic steroids (androgens), such as danazol, oxandrolone and stanozolol. However, these medications were not always effective and had signficant side effects. In some cases, they may still be prescribed to reduce the frequency of HAE attacks.

Since 2008, there are several FDA-approved medications for treating the symptoms of hereditary angioedema. These include two C1 inhibitor products, a kalikrein inhibitor and a bradykinin receptor antagonists.

Your doctor will prescribe a treatment based on several variables including the person's age, the frequency and severity of attacks, and responses to past treatments.

Newer treatments for HAE include the following:

  • Berinert® is a concentrate of C1 esterase inhibitor that has been FDA-approved for treating acute facial and abdominal HAE attacks. Berinert® is delivered intravenously.
  • Cinryze™ is a concentrate of C1 esterase inhibitor that has been FDA-approved for preventing HAE attacks. Cinryze® is administered intravenously and can be used every three or four days via home infusion for routine prevention of HAE attacks. In clinical trials, Cinryze was effective in preventing or decreasing the frequency of attacks in most, but not all HAE patients.
  • Firazyr® (icatibant) is a bradykinin receptor antagonist that has been FDA-approved for treating acute HAE attacks in patients 18 years of age and older. Firazyr® is delivered by subcutaneous injection and is approved for self-administration. It can be self-administered through an injection in the abdominal area, patients can treat themselves upon recognition of an HAE attack.
  • Kalbitor® (ecallantide) is a plasma kalikrein inhibitor that has been FDA-approved to treat acute HAE attacks in patients 16 years of age and older. Kalbitor® is delivered through subcutaneous injections. The medication’s most serious side effect is anaphylaxis, a severe allergic reaction. Other side effects include headache, nausea, diarrhea, swelling in the nose and throat, fever, and skin irritations.

During an attack, additional emergency treatment may be required to help with breathing, provide pain relief or to treat shock.

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Last updated: 1/8/2019