Hereditary Angioedema (HAE)

  • Medical Author:
    Charles Patrick Davis, MD, PhD

    Dr. Charles "Pat" Davis, MD, PhD, is a board certified Emergency Medicine doctor who currently practices as a consultant and staff member for hospitals. He has a PhD in Microbiology (UT at Austin), and the MD (Univ. Texas Medical Branch, Galveston). He is a Clinical Professor (retired) in the Division of Emergency Medicine, UT Health Science Center at San Antonio, and has been the Chief of Emergency Medicine at UT Medical Branch and at UTHSCSA with over 250 publications.

  • Medical Editor: William C. Shiel Jr., MD, FACP, FACR
    William C. Shiel Jr., MD, FACP, FACR

    William C. Shiel Jr., MD, FACP, FACR

    Dr. Shiel received a Bachelor of Science degree with honors from the University of Notre Dame. There he was involved in research in radiation biology and received the Huisking Scholarship. After graduating from St. Louis University School of Medicine, he completed his Internal Medicine residency and Rheumatology fellowship at the University of California, Irvine. He is board-certified in Internal Medicine and Rheumatology.

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Hereditary angioedema (HAE) definition and facts:

  • Hereditary angioedema (HAE) is a rare, autosomal dominant genetic disease that causes swelling of the skin and tissue just beneath the skin.
  • Some symptoms of hereditary angioedema include:
    • Swelling of the skin (most common symptom)
    • Swelling of the hands and feet
    • Fatigue
    • Headache
    • Muscle aches
    • Skin tingling
    • Abdominal pain (sometimes severe)
    • Nausea and vomiting
    • Hoarseness
    • Shortness of breath
    • Mood changes
    • Laryngeal edema (medical emergency)
    • Multiple reoccurrence symptoms
  • The cause of hereditary angioedema is due to low production of a C1 inhibitor protein, or C1-INH, (Type I HAE); or production of a faulty C1 inhibitor protein (Type II HAE). Type III is an estrogen-dependent form of HAE that is a result of mutations in the gene for coagulation factor XII.
  • HAE attacks may be triggered by many different situations including stress, anxiety, injuries, surgical or dental procedures, certain illnesses, physical activities (for example mowing the lawn), medications, menstrual periods, pregnancy and other causes.
  • HAE is diagnosed by the patient's appearance, family history, blood testing for serum C4 levels, and other complement levels such as C1, C2 and C4. Ultrasound, CT scan, and X-rays may demonstrate swelling.
  • Treatment for HAE follows the guidelines set out by the World Allergy Organization (WAO) by using C1-INH or other drugs to treat hereditary angioedema.
  • The most dangerous complication of hereditary angioedema is laryngeal edema that leads to shortness of breath or complete obstruction of the airway within a few hours.
  • Tips for managing hereditary angioedema include recommendation for the patient to carry treatments for acute HAE attacks at all times, and to consider preventative treatment when encountering a common HAE trigger, for example, a dental procedure.
  • With early diagnosis, the prognosis for individuals with hereditary angioedema range from good to fair depending on their individual disease severity and response to treatment. There is no known cure for HAE

What is hereditary angioedema (HAE)?

Hereditary angioedema (HAE) is a rare hereditary disease that causes swelling with 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.

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Causes of Swollen Lips

Swelling of the lips can be caused by a variety of different conditions. Some of the causes of swollen lips include:

  • Trauma or injury to the lip and mouth
  • Allergic reactions, either to foods, medications, or other substances
  • Angioedema (a condition in which there is swelling of the tissue beneath the skin)
  • Infections and inflammatory conditions of the skin
  • Less commonly, medical conditions or illnesses that affect the entire body

What are the symptoms of hereditary angioedema (HAE)?

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 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 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 lead to surgical exploration)
  • Nausea and vomiting
  • Diarrhea
  • Hoarseness
  • Shortness of breath
  • Mood changes
  • Swelling of the hands and feet
  • Laryngeal edema that can actually result in asphyxiation
  • Multiple reoccurrence of the above symptoms

What are the types or forms of hereditary angioedema (HAE)?

There are three forms or types of hereditary angioedema. They are distinguished by laboratory tests and genetic testing. The disease is inherited as 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.
  • Type II HAE is characterized by normal or elevated levels of dysfunctional C1 inhibitor protein.
  • Type III 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.

What causes hereditary angioedema (HAE)?

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 inhibitor (a protein that inhibits the complement system from self-activation) so that the body 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, there are various triggers that 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.

What triggers hereditary angioedema (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

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 her OB/GYN.

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Which specialties of doctors treat hereditary angioedema (HAE)?

Although the patient's primary care doctor and/or pediatrician can help manage hereditary angioedema, consultants in the specialties of genetics, internal medicine, allergists, immunologists, dermatologists and OB/GYN are frequently consulted.

How is hereditary angioedema (HAE) diagnosed?

Hereditary angioedema is sometimes difficult to diagnose because of the irregularity of attacks and because some symptoms mimic other diseases. Patients that 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.

What are the treatment guidelines for hereditary angioedema (HAE)?

The World Allergy Organization (WAO) issued the these guidelines for HAE Types I and II in 2013:

  • Assess all patients suspected of having HAE-I/II for blood levels of C4, C1 esterase inhibitor (C-INH) protein, and C1-INH function.
  • Consider on-demand treatment for all hereditary angioedema attacks that (1) result in debilitation/dysfunction and/or (2) involve the face, neck, or abdomen. Attacks affecting the upper airways must be treated.
  • Treat all hereditary angioedema attacks as early as possible with C1-INH, Kalbitor (ecallantide), or Firazyr (icatibant); do not use oral anti-fibrinolytics as on-demand treatment.
  • Consider intubation or tracheotomy early in progressive upper airway edema.
  • Administer adjuvant therapy in hereditary angioedema attacks when indicated, but use specific therapies without delay when indicated.
  • All HAE-I/II patients should have on-demand treatment for two attacks and carry their on-demand treatment at all times.
  • Plasma-derived C1-INH is the preferred on-demand therapy for HAE-I/II attacks in children and for pregnant females or women who are breastfeeding.
  • All individuals with HAE should have an action plan, product available to treat HAE attacks, and an HAE identification card.
  • Self-administration of treatment should be taught to all individuals whom are licensed for self-administration to give or be given on-demand treatment of HAE.
  • All individuals with HAE should have at least one annual assessment by an HAE specialist.

How can a person with hereditary angioedema (HAE) avoid triggers and manage the disease?

In addition, the WAO's 2013 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 an 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 health-care professional(s).

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Tips for managing and living with hereditary angioedema (HAE)

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 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 that have the same diagnosis, and they may learn other ways people with HAE have developed to manage their disease.

What are the complications of hereditary angioedema (HAE)?

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, and even some scarring in areas where the swelling has cut off or decreased blood flow to the body's tissues.

What is the prognosis for a person with hereditary angioedema (HAE)?

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 (see reference 2).

REFERENCES:

1. Frank, M.M., MD. "Hereditary Angioedema." Medscape. Updated: Feb 25, 2015.
<http://emedicine.medscape.com/article/135604-overview>

2. US Hereditary Angioedema Association. "About Hereditary Angioedema."
<http://www.allabouthae.com/professional/about-hae.aspx>

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Reviewed on 7/13/2016
References
REFERENCES:

1. Frank, M.M., MD. "Hereditary Angioedema." Medscape. Updated: Feb 25, 2015.
<http://emedicine.medscape.com/article/135604-overview>

2. US Hereditary Angioedema Association. "About Hereditary Angioedema."
<http://www.allabouthae.com/professional/about-hae.aspx>

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