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The Hereditary Angioedema Association
Frequently Asked Questions about Hereditary Angioedema
What is Hereditary Angioedema?
Hereditary Angioedema (HAE) is a rare and serious genetic condition occurring in about 1/10,000 to 1/50,000 individuals. The disease is characterized by episodes of edema (swelling) in body parts, most notably the hands, feet, face, and airway passages. In addition, patients often have bouts of excruciating abdominal pain, nausea, and vomiting that is caused by swelling in the intestinal wall.
HAE patients have a defect in the gene that controls a blood protein called C1-inhibitor. The genetic defect results in production of either inadequate or nonfunctioning C1-inhibitor protein. Normal C1-inhibitor helps to regulate the complex biochemical interactions of blood based systems involved in disease fighting, inflammatory response, and coagulation. Because defective C1-inhibitor does not adequately perform its regulatory function, a biochemical imbalance can occur and produce unwanted peptides that induce the capillaries to release fluids into surrounding tissues, thereby causing edema.
HAE is called hereditary because the genetic defect is passed on in families. A child has a 50 percent chance of inheriting this disease if one of his or her parents has it. The absence of family history does not rule out the HAE diagnosis, however. Scientists report that as many as 20 percent of HAE cases result from patients who had a spontaneous mutation of the C1-inhibitor gene at conception. These patients can pass the defective gene to their offspring.
Because the disease is very rare, it is not uncommon for patients to remain undiagnosed for many years. Many patients report that their frequent and severe abdominal pain was inappropriately diagnosed as psychosomatic, resulting in referral for psychiatric evaluation. Unnecessary exploratory surgery has been performed on patients experiencing gastrointestinal edema because abdominal HAE attacks mimic a surgical abdomen. Before therapy became available, the mortality rate from airway obstruction was reportedly as high as 30%.
What causes Hereditary Angioedema attacks?
Most attacks occur spontaneously with no apparent reason, however anxiety, stress, minor trauma, surgery, and illnesses such as colds and flu have been cited as triggers. Dental procedures make HAE patients particularly vulnerable to airway attacks. 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 is associated with an increase in the frequency and severity of attacks.
How is Hereditary Angioedema diagnosed?
Most cases of angioedema are not HAE because they are caused by something other than C1-inhibitor deficiency. Laboratory analysis or genetic testing must confirm the HAE diagnosis. There are two specific blood tests that confirm HAE:
1). C1-inhibitor quantitative (antigenic)
2). C1-inhibitor functional
Traditionally, the disease has been classified into two types. The most common form of the disease--Type I--is characterized by low quantitative levels of C1-inhibitor and affects about 85% of patients. Type II HAE affects the other 15% and is characterized by normal or elevated levels of C1-inhibitor that has abnormal function. A paper in the September 2000 volume of the British medical journal Lancet suggests there is another form of HAE that only affects females in families, but is not caused by C1-inhibitor deficiency. It has been proposed that this disease be labeled HAE Type III.
At what age do attacks of Hereditary Angioedema start?
The age of HAE onset varies considerably, however, in one study, one half of the patients reported onset of their symptoms by the age of seven, and over two thirds became symptomatic by the age of thirteen. There also seems to be an increased frequency of attacks during puberty or adolescence.
How long do Hereditary Angioedema attacks last?
Patients often report tingling or tightness at the site where edema will occur thirty minutes to several hours later. In some cases, this sensation can be present twelve to twenty four hours before the onset of swelling. Approximately one fourth of HAE patients experience a red blotchy rash both before and during an attack. The edema itself usually lasts for twenty four to seventy two hours, but the length of an attack can range from four hours to four days.
When are Hereditary Angioedema attacks considered serious?
Swelling of the extremities is uncomfortable and, according to some patients, can be painful depending on the location of the edema. Attacks that involve the face and throat must be taken seriously and medical treatment should be sought without delay. Swelling of the throat can close the air passage and cause death by suffocation. The symptoms of an impending airway obstruction include difficulty swallowing and a change in voice pitch.
Abdominal attacks cause severe pain, nausea, vomiting, and watery diarrhea. Some patients require hospitalization for low blood pressure, dehydration, and pain management. As noted above, abdominal attacks can mimic a surgical abdomen and many patients have been subjected to unnecessary exploratory surgery.
How is Hereditary Angioedema treated?
There are three types of therapy for HAE patients.
1). Long term preventive treatment
2). Short term preventive treatment
3). Treatment of acute attacks
Long term therapy is not required for all HAE patients. In some patients attacks are mild or infrequent and no long-term therapy is required. Clinicians generally recommend long term therapy for patients who experience more than one attack per month, or who believe that the disease significantly interferes with their life style. The present drugs of choice for long-term therapy are 17 alpha alkylated androgens such as stanozolol (winstrol), danazol, and oxandrolone (oxandrin). These agents produce an increase in C1-inhibitor levels, but the exact mechanism of how they do so has not been precisely defined. Some patients report success with a class of drugs called antifibrinolytics, but their use has largely been abandoned because androgens have proven more effective.
The medical literature and practitioner experience confirms that corticosteriods (prednisone), antihistamines, and epinephrine are not effective in treating angioedema created by C1-inhibitor deficiency. However, a recent study noted success using inhaled epinephrine to prevent complete airway closure.
Short-term therapy is necessary for patients who do not require ongoing treatment but are facing dental procedures or elective surgeries. Current practice calls for daily androgen therapy, during the week prior to surgery. For emergency procedures, fresh frozen plasma (preferably a product that has been treated to inactivate viruses) can be used to prevent attacks.
There is no currently approved treatment for acute attacks available in the United States. Fresh frozen plasma is used effectively by some clinicians, but this therapy is considered controversial because of a theoretical chance for attack exacerbation. C1-inhibitor concentrate is the treatment of choice for acute attacks of HAE and has been available to patients in Europe for over a decade. C1 inhibitor concentrate treatment resolves the angioedema in thirty minutes to two hours with complete remission in twenty-four hours. C1-inhibitor concentrate has not yet been approved for use in the United States notwithstanding a double blind randomized crossover study published in the New England Journal of Medicine (circa 1996) that concluded it was safe and effective for both prevention and acute attack therapy. A C1-inhibitor concentrate phase III clinical trial sponsored by Baxter Hyland Immuno is now underway in various centers throughout the United States.
The absence of an effective acute attack therapy limits clinicians to providing supportive care. Maintaining an open airway is the primary concern for patients with laryngeal edema. Because gastrointestinal edema usually involves excruciating pain and frequent vomiting, therapy should include aggressive pain management and fluid replacement. Clinicians report that Zofran, compazine, and phernergan are effective in reducing nausea and vomiting, while either morphine, demerol, dilaudid, darvocet, or stadol can be used to relieve attack related abdominal pain. Unfortunately, the HAE literature in the mid seventies made reference to patients who developed narcotic dependency and this observation was repeated in subsequent papers. Many HAE patients have noted that physicians are often wary of prescribing pain medicine for painful abdominal attacks, and this could be due to reports contained in the literature. Any notion that the HAE population suffers from widespread narcotics addiction has been discredited by the experience of researchers who have treated relatively large numbers of patients.
Are there any new treatments on the horizon?
As noted above, the treatment of choice, C1-inhibitor concentrate, is in final clinical trials and, hopefully, will be approved in the United States sometime in 2001. A partnership between Baxter Hyland Immuno and Pharming NV
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