What is Hereditary Angioedema (HAE)?

Disease Overview

Hereditary Angioedema, or HAE, is a very rare and potentially life-threatening genetic condition that involves recurrent attacks of severe swelling (angioedema) in various parts of the body, including the hands, feet, genitals, stomach, face and/or throat. Swelling in the airway can restrict breathing and be fatal. Episodes may be triggered by physical trauma or emotional stress, however, swelling often occurs without a known trigger.

Symptoms of HAE usually appear early in life, most often by age 13, and may increase in severity after puberty. Because HAE is so rare, it can take as long as a decade to obtain an accurate diagnosis after symptoms are first experienced.

When untreated, an HAE attack often lasts for three days, sometimes even longer, and many people with HAE experience three or more swelling attacks per month. The frequency and severity of attacks vary significantly among individuals, even among affected family members.

The vast majority of people with HAE have a genetic defect that causes a deficiency in the plasma protein called C1-Inhibitor. HAE is also seen in people who have normal levels of C1-Inhibitor, however, genetic defects in other genes cause their angioedema.



HAE Type I
Patients with low levels of C1-Inhibitor.
HAE Type II
Patients with adequate levels of C1-Inhibitor, but the protein does not function properly.
HAE with Normal C1-Inhibitor
In 2000, researchers discovered families with HAE that had normal levels and function of C1-Inhibitor. Subsequent research has uncovered genetic defects in 3 other genes that cause Hereditary Angioedema symptoms. These genes are Factor XII, Angiopoietin-1, and Plasminogen. There are commercial labs that can test for Factor XII mutations but genetic sequencing for Angiopoietin-1 and Plasminogen are only available in a research setting. Scientists are continuing to look for other genetic mutations that cause HAE.

Symptoms: HAE Attacks

People with HAE experience recurrent episodes of swelling in the hands, feet, genitals, stomach, face and/or throat that can last from two to five days. The frequency and severity of attacks may vary dramatically in people affected by HAE, even those in the same family. About 25% of people with HAE experience a flat, non-itching red rash that often occurs before or during an HAE attack.

It is important to remember that swelling from Hereditary Angioedema is NOT the same as swelling due to allergies and CANNOT be treated as an allergic reaction. Neither epinephrine, antihistamines, nor corticosteroids are effective in treating HAE symptoms.

Causes

The vast majority of people with HAE have a defect in the gene that controls a blood protein called C1-Inhibitor. This defect causes a biochemical imbalance that produces swelling. HAE is also known as C1-Inhibitor Deficiency- Type I and Type II. People diagnosed as having HAE with Normal C1-Inhibitor experience swelling symptoms generally similar as seen in Type I and II. US HAEA is actively funding research designed to better understand the underlying genetic and biochemical causes and find treatments for the very important members of our community who suffer from HAE with Normal C1-Inhibitor.

HAE is hereditary, and children have a 50% chance of inheriting HAE if one of the parents has the disease. However, the absence of a family history does not rule out the diagnosis of HAE, as scientific reports indicate that as many as 25% of HAE cases result from a spontaneous mutation of the C1-Inhibitor gene at conception. Children of people with HAE may also inherit the condition.

Types of HAE



HAE Type I
Representing approximately 80 to 85% of HAE cases, people with HAE Type I have levels of the C1-Inhibitor protein that are considerably below normal due to a defective gene on chromosome 11. There is usually a family history of Hereditary Angioedema, but a number of cases are due to a spontaneous mutation of the gene.

LEARN ABOUT HAE
TREATMENTS
HAE Type II
HAE Type II makes up approximately 15 to 20% of HAE cases. People with Type II have adequate or even elevated levels of the C1-Inhibitor protein, however, it does not function properly. Symptoms and treatment are the same as with HAE Type I.

LEARN ABOUT HAE
TREATMENTS
HAE with Normal C1-Inhibitor
People affected by HAE with Normal C1-Inhibitor levels and function can experience swelling generally similar to Types I and II. Scientists have found that defects in 3 other genes - Factor XII, Angiopoietin-1, and Plasminogen – cause HAE. There are commercial labs that can test for Factor XII mutations, but genetic sequencing for Angiopoietin-1 and Plasminogen are only available in a research setting. Scientists are continuing to look for other genetic mutations that cause HAE.

The HAEA is actively funding research to find a cause and, more importantly, an effective treatment for people suffering from HAE with Normal C1-Inhibitor.

Prevalence

HAE is considered a very rare disease, and occurs in about 1 in 10,000 to 1 in 50,000 people. Type I is the most common, accounting for approximately 85 percent of cases. Type II occurs in approximately 15 percent of cases. There is no data regarding the incidence of HAE with Normal C1-Inhibitor, however, expert scientists believe that the population represents a small subset of people who suffer with HAE.

Triggers

While some attacks appear to be spontaneous, some of the more common causes of HAE attacks are:

  • Anxiety
  • Stress
  • Minor trauma
  • Surgery
  • Ailments such as colds/flu/other viral infections

People with HAE have also reported swelling in extremities following:

  • Typing
  • Prolonged writing
  • Hammering
  • Shoveling
  • Other physical activities

HORMONES
In women, menstruation and pregnancy can affect HAE symptoms. Some women with HAE report an increase in the number of attacks during their menstrual periods. The scientific literature reveals that there is considerable variation in the frequency of attacks experienced by pregnant women with HAE. Use of estrogen-derived medicines, such as oral contraceptives and hormone replacement therapy, are also associated with an increase in frequency and severity of HAE attacks. People with HAE should consult with their HAE treating physician regarding alternative, non-estrogen, birth control options.
ACE INHIBITORS
Often used to treat high blood pressure, ACE Inhibitors are known to increase the frequency and severity of HAE attacks and, therefore, should be avoided.

Please consult your HAE treating physician if you are currently taking an ACE Inhibitor or any other drugs that might affect your HAE symptoms.
DENTAL PROCEDURES
Trauma to the mouth caused by dental procedures can trigger oral swelling and increase the risk of throat/airway swelling. Consult with your HAE treating physician before undergoing dental procedures.

Diagnosis

MOST cases of angioedema or swelling are NOT HAE or C1-Inhibitor deficiency.

HAE is very rare, and most people – including medical professionals – are unfamiliar with the disease until they encounter someone who has it. Even then, as symptoms come and go, it is common for people with HAE to remain undiagnosed for many years. Frequent and severe abdominal pain can easily be misdiagnosed, sometimes even resulting in unnecessary exploratory surgery.

Proper diagnosis is crucial for successful treatment and management of HAE. Laboratory analysis of blood samples, or genetic samples, are required to establish an HAE diagnosis. There are three specific blood tests used to confirm Hereditary Angioedema Type I or II:

1. C1-Inhibitor quantitative (antigenic)
2. C1-Inhibitor functional
3. C4

Genetic testing for HAE with Normal C1-Inhibitor can determine if there is a defect in one of the other three genes that have been shown to also cause HAE.

Wondering if you or someone you love might be living with undiagnosed HAE? Contact us to find a physician in your area with HAE experience who can make a diagnosis.



For a full list of Angioedema Types
Click here
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