Hereditary Angioedema (HAE)

Hereditary angioedema (HAE) is a rare hereditary disease that causes swelling with a fluid accumulation of the skin and tissues just beneath the skin (subcutaneous tissue). The disease is unique in each individual. How often the swelling occurs and how severe it is along with its location is variable. If the swelling occurs in throat tissue, it can cause a medical emergency as breathing could be inhibited or stopped by swollen tissue.

There are three forms or types of hereditary angioedema. They are distinguished by laboratory tests and genetic testing. The disease is inherited as an autosomal dominant gene, meaning only one abnormal gene is required from a parent for the offspring to inherit the disease.

• Type I HAE is caused by low levels of C1 inhibitor protein (C1-INH). This is the most common form of the disease.
• Type II HAE is characterized by normal or elevated levels of dysfunctional C1 inhibitor protein.
• Type III HAE is identified as an estrogen-dependent form of angioedema occurring mainly in women and is a result of mutations in the gene for coagulation factor XII.

The cause of hereditary angioedema is due to a problem with a gene that produces a protein termed C1 inhibitor (C1-INH). The problem with the autosomal dominant gene is that it does not produce enough C1 inhibitors (a protein that inhibits the complement system from self-activation) so that the body under certain triggers ( see below ) allows fluid to escape from tiny blood vessels into many different areas. The swelling can occur very quickly almost anywhere in the person's body.

In addition, various triggers cause an individual to have an attack of hereditary angioedema (see the triggers section). Males and females have about a 50-50 chance of inheriting the disease if one of their parents has HAE.

Although some attacks of HAE may occur for no known reason, other attacks are caused by certain triggers.

Some of the most common HAE triggers include:

• Stress
• Anxiety
• Minor injuries
• Surgical procedures
• Dental procedures
• Illnesses (for example, colds, flu, pneumonia)
• Intermittent physical activities (using a lawn mower, starting a construction project, for example)
• Medications
• Menstrual periods
• Pregnancy
• Hormone therapy

The main symptom of hereditary angioedema is swelling of the skin that does not cause itching that is experienced intermittently. Symptoms last about 2 to 5 days and then slowly decrease. Although people are born with a genetic defect, the symptoms start in childhood and worsen during the teenage years. Many people don't know they have HAE until they are diagnosed in adulthood.

These symptoms may occur with hereditary angioedema:

• Swelling of the skin (note that the above symptoms may occur before swelling begins)
• Extreme fatigue or tiredness
• Headache
• Muscle aches
• Tingling in the skin
• Abdominal or belly pain (may be extreme enough to require x-rays or even surgical evaluation)
• Nausea and vomiting
• Diarrhea
• Hoarseness
• Shortness of breath
• Mood changes
• Swelling of the hands and feet
• Laryngeal edema that can result in asphyxiation
• Multiple reoccurrences of the above symptoms

Although the patient's primary care doctor and/or pediatrician can help manage hereditary angioedema, consultants in the specialties are frequently consulted, including:

• Genetics
• Internal medicine
• Allergists
• Immunologists
• Dermatologists
• OB/GYN

Hereditary angioedema is sometimes difficult to diagnose because of the irregularity of attacks and because some symptoms mimic other diseases. Patients who have a parent with hereditary angioedema have a good possibility of inheriting the disease (about 50%), so the family genetics history is part of the diagnostic workup if hereditary angioedema is suspected.

A serum C4 level is considered a reliable and cost-effective screening test for hereditary angioedema as it is almost always decreased during attacks, and usually is low in between attacks. In addition, the three types of HAE are characterized by genetic testing and by blood tests of complement levels such as C1, C2, and C4.

Ultrasound, CT scan, and X-rays may show fluid accumulation in various tissues.

The World Allergy Organization (WAO) issued these guidelines for HAE Types I and II in 2017 (updated 2021):

• Assess all patients suspected of having HAE-I/II for blood levels of C4, C1 esterase inhibitor (C-INH) protein, and C1-INH function; if any levels are low, repeat the tests.
• Consider on-demand treatment for all hereditary angioedema attacks. Attacks affecting the upper airways must be treated.
• Treat all hereditary angioedema attacks as early as possible. C1-INH, Kalbitor (ecallantide), or Firazyr (icatibant) are recommended treatments.
• Consider intubation or tracheotomy early in progressive upper airway edema.
• All HAE-I/II patients should have on-demand treatment for two attacks and carry their on-demand treatment at all times.
• Short-term prophylaxis is recommended before doing procedures that can induce an attack.
• Prophylaxis is recommended before patients face events that are associated with the increased disease.
• Evaluation for long-term prophylaxis is recommended for patients at every clinic visit.
• A CC1-inhibitor is recommended as a first-line treatment long-term therapy for patients.
• Androgens are recommended as a second-line treatment long-term therapy for patients.
• Long-term therapy for patients with adjusted doses and/or treatment intervals is recommended.
• Testing children from HAE-affected families be done ASAP.
• Plasma-derived C1-INH is the preferred on-demand therapy for HAE-I/II attacks in children under 12. and for pregnant females or women who are breastfeeding.
• All individuals with HAE should have an action plan, a product available to treat HAE attacks, and an HAE identification card.
• Self-administration of treatment should be taught to all individuals who are licensed for self-administration to give or be given the on-demand treatment of HAE.
• All individuals with HAE should have at least one annual assessment by an HAE specialist to have comprehensive and integrated care.
• Patient education about HAE triggers.
• Family members of patients with HAE should be screened for the disease.

Note that since the 2017 guidelines were published, the FDA approved the use of the subcutaneous administration of Haegarda, a C1 esterase inhibitor, for use in patients 6 years and older. It reportedly reduced HAE attacks by about 95% and may be added when the guidelines are reviewed.

What about pregnancy and hereditary angioedema (HAE)?

Females who are pregnant and have abdominal pain may be difficult to diagnose, but they can be treated with the same medications as other hereditary angioedema patients in consultation with their OB/GYN.

In addition, the WAO's 2013-2017 recommendations regarding prophylaxis and screening in hereditary angioedema are:

• Consider administering short-term pre-procedural prophylaxis, particularly in cases involving dental/intraoral surgery, bronchoscopy or endoscopy, endotracheal intubation, or manipulation of the upper airway or pharynx.
• Before beginning long-term prophylaxis with androgens, a person with HAE should be assessed for cardiac risk factors, and obtain a complete blood count (CBC), urine analysis, liver function test results, lipid profile, and liver ultrasonography.
• During the use of androgens for long-term prophylaxis, and for 6 months after cessation of therapy, the person's CBC, urine analysis, lipid profile, liver function test results, and blood pressure should be monitored every 6 months, and annual ultrasonography of the liver should be performed.
• Defer screening children for HAE-I/II until the age of 12 months. Test all offspring of an affected parent.
• Family members of people with HAE (I or II) should be screened so that appropriate therapy can be available for treatment.
• People with HAE-I/II receiving blood products including Plasma-derived C1-INH should receive a hepatitis A and B vaccination. All individuals with HAE-I/II should receive an influenza vaccine.
• Guidelines are subject to change as newer drugs and modifications of treatment protocols are made available. People with HAE are urged to discuss their treatments and treatment changes, if any, with their healthcare professional(s).
• Since the 2017 guidelines were published, the FDA approved the use of the subcutaneous administration of Haegarda, a C1 esterase inhibitor, for use in patients 6 years and older. It reportedly reduced HAE attacks by about 95%.

Parents of children and teenagers should discuss their child's diagnosis with all family members and caregivers so that they are well-informed about the disease. It is especially important to know what to do if there's any swelling in the throat because that constitutes a medical emergency.

• Share your medical history (especially that you have HAE) with emergency medical responders, because it could be lifesaving. Symptoms like laryngeal swelling mimic allergic responses, and medications such as epinephrine or cortisone, commonly used to treat allergic reactions, have little or no effect on hereditary angioedema-induced laryngeal swelling.
• As stated by the WHO previously, people with hereditary angioedema should carry with them two treatments for acute HAE attacks at all times. It may be useful to keep a notebook about hereditary angioedema attacks so that you or your child can begin to identify triggers that precipitate HAE.
• As previously noted, there are some common triggers (surgery, dental procedures, for example) of HAE. Consequently, it is possible to prophylactically treat people with HAE in advance of these potential triggers to avoid a hereditary angioedema attack.
• Remember that it is possible to recognize some symptoms that occur in some individuals just before an HAE attack starts. Recognizing those symptoms in an individual can allow them to treat themselves immediately to stop or lessen symptoms of HAE.
• Once diagnosed with hereditary angioedema, with the help of their health care professional(s), people with HAE and/or their family members may be put in contact with others who have the same diagnosis, and they may learn other ways people with HAE have developed to manage their disease.
• Become familiar with your disease, and educate everyone around you about your disease.
• Utilize resources such as the US Hereditary Angioedema Association https://www.haea.org.

There is no known cure for hereditary angioedema. The prognosis for an individual with hereditary angioedema ranges from good to fair. Those who are undiagnosed have a poorer prognosis as they may receive treatments for symptoms of hereditary angioedema that simply are not effective.

Once diagnosed, better awareness of their disease process and current medications allow optimal control and/or management of symptoms. Research in hereditary angioedema is ongoing.

The most dangerous complication of hereditary angioedema is laryngeal edema, which can result in a rapidly advancing shortness of breath to complete airway obstruction within a few hours.

Other complications can include:

• Visual disturbances
• Difficulty walking
• Scarring in areas where the swelling has cut off or decreased blood flow to the body's tissues