Sandy is 25 and just started teaching at a new school. She has had peanut allergy, allergic rhinitis (hayfever) and asthma since childhood. She hasn't had a reaction to a food in years. She always carries her epinephrine autoinjector. However, for the last few years she has had episodes of abdominal pain sometimes with vomiting that last a few days. She hasn't been able to pinpoint a food that causes these episodes. A few months ago she had an episode of severe swelling of her tongue without any itching and she had not eaten anything unusual. She took her epinephrine autoinjector and went to the ER. Despite steroids and antihistamines the swelling persisted and took 3 days to disappear. She was referred to an allergist/immunologist who found she had both low C4 level and a low CI inhibitor level. She was diagnosed as having Hereditary Angioedema Type 1 in addition to her other problems.
Hereditary angioedema (HAE) is a rare genetic disorder occurring in 1:10 000 to 1:50 000 people characterized by episodes of swelling in different areas of the body including the skin, respiratory tract and the mucosal surface of the gastrointestinal tract. It affects men and women equally and patients often don't present with symptoms until adolescence or even later in life even though they are born with the condition. While allergic rhinitis affects 1 in 3 Canadians, asthma 1in 9 and peanut allergy 1.5 in 100, hereditary angioedema is very rare.
In hereditary angioedema, swelling of the skin occurs mainly in the face although the extremities and genitals are also often affected. In many cases, patients experience swelling and tightness of the skin or a tingling sensation, and in some cases pain, but it is usually not described as itchy. The swelling is due to unregulated production of bradykinin which causes a deep tissue swelling. These episodes can be brought on by minor injury, surgery, allergic reactions and on some occasions with no obvious precipitating cause. Abdominal pain from intestinal swelling is usually the most common type of swelling for patients.
Swelling of the mucous membranes of the larynx, throat or tongue is potentially life-threatening, and can cause death. Symptoms that are felt just before an attack in the throat may include trouble swallowing, a hoarse voice, a swollen tongue, cough, or shortness of breath. Patients who experience these symptoms should seek emergency attention immediately. More than half of HAE patients will have at least one laryngeal swelling edema in their life.
The development of angioedema does not follow a typical pattern and therefore the site of the next episode of swelling cannot be predicted. The frequency, duration and severity of the edema vary considerably. About 1 in 3 patients experience more than one 1 attack per month; about 40% have about 6-11 attacks per year and the remaining 22% only suffer attacks infrequently from time to time. In most cases, the symptoms of HAE increase over 12 to 36 h and last for 2-5 days before resolving. However, some patients may experience attacks that last over 7 days. Some patients have such frequent attacks it is difficult for them to attend school or work.
Most HAE attacks occur spontaneously, but patients can often link specific situations that occur in their lives, such as stress, infections, surgey, trauma or allergic reactions, to the development of angioedema.
Under normal conditions, C1inhibitor regulates the body's production of bradykinin, a protein that acts locally to cause swelling in response to an injury or infection. If the C1 inhibitor level is too low or doesn't function properly, bradykinin is formed resulting in local swelling or angioedema.
Drugs that lower blood pressure (ACE inhibitors) can mimic hereditary angioedema. ACE inhibitors prevent bradykinin from being broken down once it is formed. They can also make any allergic reaction more severe in the same way. If someone has swelling on an ACE inhibitor an alternate drug should be found. If there is a history of anaphylaxis ACE inhibitors should be avoided.
The diagnosis was confirmed by measurement of the certain proteins in the blood. Patients with the most common type of HAE (Type 1) lack a protein called C1esterase inhibitor. Without this protein they also tend to have low C4 levels. Since it is easier to measure C4 we use this as a screening test. A less common form of HAE (Type II) is due to poor function of the C1inhibitor protein. Although the level may be normal the protein doesn't function properly. They also have a low C4 level. Another type of HAE (Type III) usually only occurs in women with attacks generally occurring around the menstrual cycle. Their C1 inhibitor and C4 levels are normal and their C1 inhibitor functions normally but they have very similar attacks. Genetic testing may be helpful. There are also acquired forms of angioedema that occur later in life and are not genetic nor allergic.
Should an exacerbation of angioedema occur, C1 inhibitor concentrate (Berinert or Cinrzye) is the treatment of choice especially if symptoms are severe (i.e., involve the throat, difficulty breathing, bowel obstruction). After administering, the swelling/abdominal pain should start to decrease in 30 minutes and will usually completely resolve within 24 hours. This product is available through the blood bank and is given quickly intravenously.
Icatibant (Firazyr) is a new product just approved in Canada. It is a protein which can be given subcutaneously. It is a bradykinin receptor antagonist. It can turn off the effects of bradykinin and reduce swelling.
To reduce the number of attacks, attenuated androgens such as Danazol can be taken on a regular basis recognizing it can cause virilisation, irritability and hypertension. It is recommended that the smallest amount of Danazol be used daily that reduces the number of angioedema episodes. Regular monitoring of blood work, in particular, liver function tests is required while taking Danazol since it may increase one's risk of hepatocellular cancer as well. Tranexamic acid can also be tried to prevent attacks but it can increase the risk of thrombosis.
Prednisone, antihistamines and epinephrine are usually unhelpful in HAE unless the event was triggerd by an allergic reaction.
With abdominal HAE attacks the patient may require IV rehydration and pain management in addition to the treatment plan outline above.
All patients with HAE should wear a bracelet or necklace identifying their medical condition.
Depending on the extent of the surgery or operative procedure, it may be necessary to give C1 inhibitor concentrate intravenously1 hour prior to the procedure. The clinical effect generally lasts about 3 days. 2 additional doses of C1 inhibitor concentrate should be readily available
HEREDITARY ANGIOEDEMA SCREENING
Once a diagnosis of hereditary angioedema is confirmed, it is recommended that the patient's children also be screened for the presence of the deficiency particularly if they too are experiencing swelling. Hereditary angioedema is inherited in an autosomal dominant fashion so in general 50% of offspring will be affected. HAE can also arise as a spontaneous mutation and there may be no family history. Screening is performed by blood test.
What happened to Sandy?
Sandy tried low doses of danazol to prevent her symptoms but the side effects of virilisation and irritability forced her to stop. Tranexamic acid did little to reduce her episodes. Since her episodes became more and more frequent and she was spending more and more of her time in the emergency room requiring C1 inhibitor intravenously she began training how to give herself C1 inhibitor intravenously at home. Having become proficient at this she is now able to administer her C1 inhibitor early in an attack and reduce the severity and duration of her episodes of swelling. She also carries Icatibant syringes with her in case she is unable to start an IV to administer her C1 inhibitor. Of course she also carries her epinephrine in case she accidentally ingests peanut but she is very good at reading labels and fortunately hasn't had symptoms due to food allergy in years.
"What is Hereditary Angioedema" Slides
Bowen T, Brosz J, Brosz K, et al. Management of hereditary angioedema: 2010 Canadian approach. Allergy, Asthma & Clinical Immunology 2010;6:20.