Frequently asked questions (FAQ)

  1. What is angioedema
  2. Are there visible differences between histamine-mediated and bradykinin-mediated forms of angioedema?
  3. I have suffered since childhood with recurrent cramping abdominal pain. Sometimes, but not always, I also have swelling of the skin on my face or hand. Could these be symptoms of a form of angioedema?
  4. How dangerous is angioedema?
  5. How does angioedema of the skin manifest itself?
  6. What is the treatment for histamine-mediated angioedema?
  7. What is the treatment for bradykinin-mediated angioedema?
  8. What do you mean by “Not every case of angioedema is alike”?
  9. What is histamine-mediated angioedema?
  10. What is bradykinin-mediated angioedema?
  11. What causes hereditary angioedema (HAE)?
  12. What is a “new mutation”?
  13. How frequent is hereditary angioedema (HAE)?
  14. How do I find out if I am taking an ACE inhibitor or AT-1 blocker?
  15. Why do ACE inhibitors trigger angioedema?
  16. My mother has been taking an ACE inhibitor for seven months. Recently, she for the first time experienced severe swelling of the lip that resolved by itself after about two days. Could the medication be the cause of this?
  17. What are “RAAS inhibitors”?
  18. Why does bradykinin cause swelling?
  19. Are there warning signs that point to an impending swelling attack?
  20. Is there a typical age at which bradykinin-mediated angioedema first occurs?
  21. Does the swelling associated with bradykinin-mediated angioedema resolve on its own (i.e., without treatment)?
  22. What are typical symptoms of angioedema that affects the mucous membranes of the gastrointestinal tract?
  23. What are signs of swelling affecting the larynx?
  24. Are there everyday situations that can trigger swelling attacks?
  25. Does bradykinin-mediated angioedema always require treatment with medication?
  26. How is an acute attack of hereditary angioedema treated?
  27. Can changes in women’s hormone levels trigger swelling attacks?
  28. What do parents need to do if their child is diagnosed with hereditary angioedema (HAE)?

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What is angioedema?

Angioedema is a swelling of the deeper layers of the skin and/or mucous membranes. It can develop in any region of the body. Most commonly affected are circumscribed areas of the face, hands, feet, arms, legs and genital organs. The trunk, however, may also be affected by angioedema.

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Are their visible differences between histamine-mediated and bradykinin-mediated forms of angioedema?

As a rule, bradykinin-mediated angioedema develops gradually over the course of several hours. This differs from histamine-mediated angioedema, which achieves its full severity much more quickly. Also, in contrast to histamine-mediated angioedema, the swelling in bradykinin-mediated angioedema is not associated with wheals or pruritus (itching).

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I have suffered since childhood with recurrent cramping abdominal pain. Sometimes, but not always, I also have swelling of the skin on my face or hand. Could these be symptoms of a form of angioedema?

Yes, these symptoms may represent evidence of a form of angioedema. Sometimes, gastrointestinal complaints are the only signs of the disease in the absence of visible swelling of the skin. In such cases, differentiating between angioedema and other disorders affecting the gastrointestinal tract can be difficult. Frequently, symptoms are wrongly ascribed to other, more common disorders, such as appendicitis or gastric ulcer. This can sometimes result in patients undergoing unnecessary surgical procedures. Gastrointestinal symptoms are especially typical for hereditary angioedema (HAE).

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How dangerous is angioedema?

Angioedema can be dangerous when it affects tissues around the airways. Swellings of the larynx and severe swellings of the tongue compromise breathing and, if not treated promptly, may even result in death by asphyxiation. In emergency situations, you should summon emergency medical assistance directly from the emergency services by dialling 112, 999, 911 or the emergency number established for your area. Patients with a known bradykinin-mediated form of angioedema should inform the emergency physician or ambulance medic of this fact so that the appropriate treatment can be immediately administered. It is best to always carry an emergency identification card listing the diagnosis and treatment recommendations as well as emergency medication.

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How does angioedema of the skin manifest itself?

Areas most commonly affected by swellings include the face, hands, feet, arms, legs and genital organs. In persons with bradykinin-mediated angioedema, swellings develop gradually over the course of several hours. In addition, pruritus (itching) is usually absent, although these kinds of angioedema are often associated with a feeling of tightness and sometimes also with pain.

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What is the treatment for histamine-mediated angioedema?

These swellings respond well to antihistamines, corticosteroids (“cortisone”) and, in emergency situations, adrenalin.

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What is the treatment for bradykinin-mediated angioedema?

Two treatment methods are available for sudden attacks in patients with the much less common bradykinin-mediated angioedema:

  • Icatibant, a bradykinin receptor antagonist, which is injected into the subcutaneous adipose tissue
  • C1-esterase inhibitor (C1-INH) concentrate, which is injected into a vein or given as an intravenous infusion

Patients may also receive medication prior to elective surgeries or dental treatments in order to reduce the risk of swelling attacks. IMPORTANT: Antihistamines and corticosteroids (cortisone) are ineffective in treating bradykinin-mediated angioedema.

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What do you mean by “Not every case of angioedema is alike”?

There are different forms of angioedema with different causes that are treated differently. It is, therefore, important to look for and find the underlying cause of each patient’s swelling attacks. Depending of their cause, the different forms of angioedema are classified as follows:

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What is histamine-mediated angioedema?

Angioedema is frequently seen in association with urticaria allergic reactions. Very typically, the swelling is accompanied by the development of wheals and pruritus (itching). During a urticaria or an allergic reaction, the body releases a protein known as histamine. Among its many actions, histamine acts to temporarily increase the permeability of the vascular walls, allowing increased amounts of fluid to escape from the blood vessels and enter the surrounding tissues. This results in swelling. This type of angioedema is therefore described as histamine-mediated angioedema.

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What is bradykinin-mediated angioedema?

Much less common is angioedema due to a genetic defect or caused by treatment with certain cardiovascular medications. In these forms of angioedema, bradykinin, a protein produced by the body, plays a central role. Bradykinin increases the permeability of the blood vessels, allowing fluid to escape from the vessels and enter the surrounding tissue and leading to angioedema. The forms of bradykinin-mediated angioedema include both hereditary angioedema (HAE) and different forms of acquired angioedema (AAE).

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What causes hereditary angioedema (HAE)?

Hereditary angioedema (HAE) is caused by a change (mutation) in the genetic information of the affected individual. The mutation affects a gene located on chromosome 11, which is responsible for the synthesis of the C1-esterase inhibitor (C1-INH). C1-INH is an important protein that regulates a variety of metabolic processes in the body. Persons with hereditary angioedema (HAE) produce either too little C1-INH or a form of C1-INH that does not function correctly. Among other functions, C1-INH acts to prevent the excessive production of bradykinin in association with inflammation, coagulation reactions and other processes in the body. Bradykinin increases the permeability of the blood vessel wall. If the synthesis of bradykinin is not kept within its proper limits by C1-INH, angioedema attacks may occur.

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What is a “new mutation”?

In some cases, an inherited disorder may have no known family history. In these cases, the mutation responsible for the disorder may occur spontaneously without there being any history of cases of the disease in the family. This is known as a “new” or “de novo mutation”.

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How frequent is hereditary angioedema (HAE)?

HAE is a rare but important disease entity. Worldwide, it is estimated that about 2-4/100,000 persons are affected. In Europe, 10,000 to 50,000 persons suffer from HAE; of these about 1,200 live in Germany. Experts, however, suspect that the number of unrecognised cases may be much higher. This is because the symptoms of HAE often resemble those of other more common diseases and the general familiarity with this disease is low. The vast majority of HAE patients experience their first swelling attack before the age of 30 years, sometimes even in infancy. Men and women suffer from the disease in about equal numbers.

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How do I find out if I am taking an ACE inhibitor or AT-1 blocker?

Examine the package insert of your medication. At the top, you will see the name of the active agent (the “generic name”).

  • The generic or chemical names of ACE-inhibitors end in “-pril”, for example: benazepril, captopril, cilazapril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril, trandolapril.
  • The generic or chemical names of AT-1 antagonists end in “-sartan”, for example: candesartan, losartan, valsartan.

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Why do ACE inhibitors trigger angioedema?

Swelling attacks occurring in patients taking ACE inhibitors or AT-1 blockers are also mediated by bradykinin. This is because these medications inhibit the break-down of bradykinin, leading to an increase in the bradykinin concentration followed by increased permeability of the vascular wall and, sometimes, the development of angioedema.

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My mother has been taking an ACE inhibitor for seven months. Recently, she for the first time experienced severe swelling of the lip that resolved by itself after about two days. Could the medication be the cause of this?

Yes, this is possible. About 0.1-0.6% of patients treated with ACE inhibitors develop angioedema. About half of affected patients develop angioedema within the first two months after starting the medication. Swelling attacks may, however, occur after months or even years of well-tolerated use of the medication.

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What are “RAAS inhibitors”?

Both angiotensin converting enzyme (ACE) inhibitors and and angiotensin receptor (AT-1) blockers act to inhibit steps in the Renin-Angiotensin-Aldosterone System (RAAS) and are, therefore, grouped under the main heading of RAAS inhibitors. They are used in the treatment of hypertension (high blood pressure) as well as for cardiac insufficiency, following a myocardial infarction (heart attack) or renal insufficiency.

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Why does bradykinin cause swelling?

Bradykinin plays the key role in the development of swelling in persons with bradykinin-mediated angioedema. Bradykinin, whose physiological function is similar to that of histamine, is produced in the body as a result of activation of the kallikrein-kinin system. The kallikrein-kinin system consists of a chain of different proteins in the blood which affect or control numerous processes and reactions in the body, including inflammation, coagulation, blood pressure and pain. Bradykinin causes a dilatation of the blood vessels and increases the permeability of the vascular wall. This allows increased amounts of fluid to pass from the blood vessel into the surrounding tissue. The result can be a non-pruritic (non-itching) swelling of the skin or mucous membranes.

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Are there warning signs that point to an impending swelling attack?

Many swelling attacks are preceded by warning signs, also known as prodromes. The most well-known precursor is erythema marginatum, which is characterised by patches of erythema (skin reddening) that are non-pruritic (not itchy) and often annular (ring-like) in shape. They precede about 25% of swelling attacks. The subsequent swelling, however, does not always appear at the same site. Further prodromes include tingling in the skin, mood variability as well as anxiety and exhaustion.

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Is there a typical age at which bradykinin-mediated angioedema first occurs?

Signs and symptoms of hereditary angioedema (HAE), including, for example, abdominal pain, can occur in early childhood. In many cases, symptoms first manifest during puberty, a period during which the frequency and severity of attacks often increases. Despite the early age of onset, the diagnosis of HAE is typically made much later because the disease is often not immediately recognised. If, however, symptoms first appear after the age of 30 years and no family members suffer from similar symptoms, other forms of angioedema must also be considered.

 

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Does the swelling associated with bradykinin-mediated angioedema resolve on its own (i.e., without treatment)?

If left untreated, bradykinin-mediated angioedema typically persists for 24 to 72 hours and then resolves spontaneously. In some cases, however, an attack may last as long as seven days.

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What are the typical symptoms of angioedema that affects the mucous membranes of the gastrointestinal tract?

Swelling attacks affecting the gastrointestinal tract manifest with cramping pain, nausea, vomiting and/or diarrhoea.

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What are signs of swelling affecting the larynx?

Swelling attacks involving the mouth or neck can be life-threatening, especially when they affect the larynx (voice box). In some cases, the airways may be completely obstructed within less than four hours. There is acute danger of asphyxiation and death. The first signs of impending angioedema in the laryngeal area include a feeling of a foreign body in the throat coupled with problems swallowing (dysphagia) and changes in the voice such as hoarseness, followed by a whistling noise during breathing (stridor). Any suspicion of impending or developing swelling of the larynx should prompt you to seek out a physician immediately. In such situations, you should summon emergency medical assistance directly from the emergency services by dialling 112, 999, 911 or the emergency number established for your area. Patients with a known bradykinin-mediated form of angioedema should inform the emergency physician or ambulance medic of this fact in order that the appropriate treatment can be immediately instituted. It is best to always carry an emergency identification card listing the diagnosis and treatment recommendations as well as emergency medication.

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Are there everyday situations that can trigger swelling attacks?

In many cases, angioedema attacks occur spontaneously. Still, research has identified a number of factors that may be implicated in the development of an angioedema attack. These include surgical procedures, dental treatments, emotional stress and, in women, changes in oestrogen levels (e.g., during the menstrual cycle). Other potential triggers include physical exercise, prolonged sitting or standing, excessive heat or cold, contact with certain chemicals, infectious disorders (including colds), certain foods, sudden changes in meteorological conditions and medications that contain oestrogen (oral contraceptives, hormone replacement therapy). In most cases, however, attacks begin without any identifiable trigger, thus impacting patients without prior warning.

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Does bradykinin-mediated angioedema always require treatment with medication?

Whether or not it is necessary to treat symptoms of bradykinin-mediated angioedema depends on the degree to which a given patient is burdened—or endangered—by the disorder. The decision in favour of using medication to counter swelling attacks must be made on the basis of a comprehensive and frank consultation between physician and patient. Acute therapy (i.e. treatment during an attack) with medication is recommended in

  • Severe to life-threatening swelling attacks (e.g. attacks affecting the laryngeal area)
  • Painful gastrointestinal attacks
  • Disabling swelling that interferes with activities of daily life

Patients can also be offered the option of short-term prophylaxis, consisting of a time-limited treatment with medication aimed at reducing the risk of swelling associated with known triggers of angioedema, such a dental treatments or surgical procedures.

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How is an acute attack of hereditary angioedema treated?

There are two currently available options for the treatment of acute angioedema attacks:

  • Administration of the bradykinin B2-receptor antagonist, icatibant. Bradykinin, which increases the permeability of the vascular wall for fluid, is present in abnormally high quantities in patients with HAE. Icatibant blocks the bradykinin B2 receptors in the cells of the blood vessel walls, which in turn prevents the swelling caused by the actions of bradykinin. The medication is injected into the subcutaneous adipose tissue.
  • Administration of C1-esterase inhibitor (C1-INH) concentrate. Patients with HAE have too little C1-esterase inhibitor (C1-INH) or the C1-INH present in their systems does not function correctly. Because of this deficiency, the body produces excessive amounts of bradykinin, with the result that they are at risk of swelling of the skin and mucous membranes. C1-INH concentrate is either injected into a vein or administered as an intravenous infusion.

In addition to these options, a number of other treatment concepts are currently being tested. IMPORTANT: Antihistamines and corticosteroids (cortisone) are ineffective in the treatment of hereditary angioedema (HAE).

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Can changes in women’s hormone levels trigger swelling attacks?

Yes, this may occur. Among the known triggers of angioedema are hormonal changes in women. At times of significant change in their hormone levels, women should especially be on their guard for signs and symptoms of angioedema. For example, many women experience their first angioedema attacks during puberty. Attacks may become more frequent and intense in association with the use of medications containing oestrogens (oral contraceptives, hormone replacement therapy). Other periods of increased risk include the time during or after pregnancy and during the menopause.

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What do parents need to do if their child is diagnosed with hereditary angioedema (HAE)?

In order to help an affected child deal with swelling attacks as effectively as possible, parents should adopt a pro-active approach to their child’s illness. This includes:

  • The child’s caregivers and teachers must be informed of the disease.
  • Telephone numbers and other contact information of involved parties (parents, relatives, physician, HAE center or clinic) must be available for emergency reference to everyone working with the child.
  • Teachers and chaperones accompanying the child on outings, field trips and other activities should be provided with copies of the child’s emergency identification card, emergency medications and, when necessary, with a letter from the physician or clinic.
  • In the case of longer trips, consider finding and contacting a local hospital or physician to discuss arrangements in an emergency.

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