Angioedema causes
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Angioedema is most commonly caused by an allergic reaction, although medications, genetics, and other immune system disorders may also cause the condition.
The disease is marked by swelling that occurs as a result of a buildup of fluid in the deeper layers of the skin or mucous membranes. Regardless of the underlying cause, this is generally driven by small blood vessels becoming more permeable, or leaky, which allows fluid to escape and build up in nearby tissues.
Angioedema swelling, or edema, can affect any part of the body, but most commonly affects the face, hands, feet, or genitals. When it affects the throat, angioedema can cause problems breathing and may be a medical emergency.
There are multiple types of angioedema. All are marked by swelling, but the underlying angioedema causes and disease management differ from type to type. Other angioedema symptoms that can co-occur with swelling, such as itching, hives, or abdominal pain, also may vary among the different angioedema types. Due to these differences, disease management will also vary by type.
Common causes of angioedema
Angioedema most commonly occurs due to allergic reactions, or as a side effect of certain medications.
Allergies
Angioedema can be triggered by an allergic reaction, which happens when the body’s immune system wrongly recognizes a harmless substance as a threat and launches an inflammatory response against it. This specific form of the condition is known as acute allergic angioedema.
As part of the allergic response, immune cells — especially mast cells — become activated and release signaling molecules that increase blood vessel permeability, ultimately leading to swelling. A signaling molecule called histamine plays a central role in this type of angioedema, which is also the reason why angioedema treatment for these patients commonly involves the use antihistamines — medicines that block histamine.
Just about any allergen — a substance that can trigger an allergic reaction — can cause angioedema. Some of the specific substances that have been reported to cause acute allergic angioedema include:
- foods, especially nuts, shellfish, milk, or eggs
- medications such as penicillin and certain other antibiotics (e.g., sulfa drugs), or aspirin
- insect venom from a bite or sting
- latex gloves, or other latex products.
Medications
Some medications may cause swelling as a side effect, even if a person is not allergic to them. This type of drug-induced angioedema is sometimes referred to as nonallergic angioedema.
One of the most common causes of drug-induced angioedema is angiotensin-converting enzyme (ACE) inhibitors, a type of medicine normally used to treat high blood pressure. Examples include enalapril (marketed as Vasotec and others) and lisinopril (marketed as Zestril and others). These medications work by preventing the breakdown and increasing the levels of bradykinin, a signaling molecule that prompts blood vessels to widen, thus lowering blood pressure. Bradykinin also increases blood vessel permeability, which can cause edema.
Another class of medications used to lower blood pressure, called angiotensin-receptor blockers (ARBs), also may cause this type of angioedema. Examples include losartan (marketed as Cozaar and others) and valsartan (marketed as Diovan and others). Generally, angioedema associated with ARBs is less severe and occurs earlier than angioedema caused by ACE inhibitors.
Other types of medications can cause nonallergic angioedema in rare instances. These include statins, which are cholesterol-lowering medicines, and nonsteroidal anti-inflammatory drugs (NSAIDs), a class that includes over-the-counter pain medicines like ibuprofen, which are commonly used to control mild inflammation.
Less common causes of angioedema
In rarer cases, angioedema can be caused by genetic mutations or arise due to a malfunction of the immune system. There also are instances of angioedema where the specific underlying cause is not known.
Genetics
Hereditary angioedema (HAE) is a rare chronic genetic disorder characterized by recurrent swelling attacks. HAE is caused by mutations that are most commonly inherited from a person’s biological parents. However, in as many as 1 in 4 cases, HAE can occur in people without a family history of the disease due to mutations that arise spontaneously in sperm or egg cells prior to conception.
The most common forms of HAE — types 1 and 2 — are caused by mutations in the SERPING1 gene, which provides instructions for making a protein called C1-inhibitor (C1-INH). This protein normally helps to counteract a chain of events that trigger the production of bradykinin. Hereditary angioedema medications generally work to reduce bradykinin levels, which can help to prevent swelling.
In HAE type 1, which accounts for 80%-85% of all cases, mutations in SERPING1 impair the production of the C1-INH protein, causing its levels to drop too low. In HAE type 2, which accounts for the vast majority of other documented HAE cases, the protein is made, but does not function properly.
HAE type 3 encompasses cases that are caused by mutations in genes other than SERPING1. In some cases, HAE type 3 is caused by mutations in the F12 gene, which provides instructions for making a protein called clotting factor 12 that helps control bradykinin production. Mutations in F12 can cause the factor 12 protein to become overactive, resulting in abnormally high bradykinin levels and swelling. [S]
Mutations in a few other genes, including PLG, ANGPT1, KNG1, MYOF, and HS3ST6, have also been linked to HAE type 3, though they are still poorly understood.
Other causes
Acquired angioedema is a very rare condition marked by abnormally low C1-INH levels, leading to the excessive production of bradykinin and swelling, much like HAE type 1. However, whereas HAE is caused by mutations a person is born with, acquired angioedema develops during a person’s lifetime as a result of other health conditions.
Type 1 acquired angioedema affects some people with lymphoproliferative disorders — diseases where immune cells grow out of control — including some autoimmune conditions and cancers. Acquired angioedema can develop in people with these disorders due to the excessive activation of a protein called C1. Normally, C1-INH blocks the activity of C1, and in these diseases, the body’s store of C1-INH gets spent as it tries to correct the excessive C1 levels. The end result is low C1-INH levels that set the stage for angioedema.
Type 2 acquired angioedema develops as a result of an autoimmune condition in which the body’s immune system mistakenly identifies the C1-INH protein as a potential threat. When this happens, antibodies that target and neutralize the C1-INH protein are produced, ultimately leading to angioedema.
There also are some cases in which the underlying cause of angioedema cannot be determined. This specific form of angioedema, known as idiopathic angioedema, is diagnosed only when all other potential explanations for swelling have been ruled out. The term “idiopathic” means “of unknown origin.”
Risk factors
Several factors may increase a person’s risk of experiencing angioedema swelling. Angioedema risk factors may include demographic characteristics like age, gender, and ethnicity, as well as clinical factors such as allergies or disease family history.
Allergies
Given that acute allergic angioedema is caused by allergies, people with a history of allergic reactions are at a higher risk of developing this type of angioedema. If a prior allergic reaction to a certain substance has caused angioedema, it’s likely that subsequent exposure to the same substance will again cause swelling. For this reason, people who experience these reactions are advised to avoid being exposed to the trigger substance to prevent future swelling episodes.
Medications
While some medications cause angioedema by triggering an allergic reaction, there are others, especially ACE inhibitors, that can cause drug-induced or nonallergic angioedema as a side effect. Patients are advised to talk to their doctor about the potential risks associated with any medication they are prescribed. If unexplained swelling occurs, medical care should be sought at once.
Age, gender, and ethnicity
Nonallergic angioedema associated with the use of ACE inhibitors appears to be more common in women than in men, as well as in adults older than 65. It’s also been reported that the risk of experiencing ACE inhibitor-induced angioedema is much higher in people who are Black.
Family history
Because mutations that cause hereditary angioedema are mostly inherited from a person’s biological parents, having a family history of HAE is a major risk factor for the disease.
Most cases of HAE are inherited in an autosomal dominant manner, meaning that one mutated copy of a gene is sufficient to cause the disease. If a person with HAE has a biological child, there’s a 50% chance that the child will also have HAE.
Angioedema News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
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