Causes of Angioedema

Characterized by swelling in the deep layers of the skin or mucous membranes, angioedema is most commonly caused by small blood vessels becoming more permeable, or leaky. The fluid that leaks from these vessels builds up in surrounding tissues, causing swelling or edema.

Such swelling usually occurs in the area around the eyes, lips, tongue, hands, feet, and/or genitals. In more severe cases, the swelling may affect the upper respiratory tract or intestines.

Angioedema can be triggered by a variety of factors, including allergic reactions, medications, and inherited genetic mutations. There are several different types of angioedema for which the underlying cause may differ, but the end result — swelling — is the same.

There also is a type of angioedema, called idiopathic angioedema, in which the exact cause is unknown. Research suggests that some cases of idiopathic angioedema may be associated with autoimmune disorders like systemic lupus erythematosus.

Allergic reactions

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. As part of this response, immune cells — particularly mast cells — become activated, and release signaling molecules that increase the leakiness of small blood vessels, in turn causing edema.

Specific substances that can trigger this type of allergic angioedema include foods, especially nuts, shellfish, milk, or eggs, and medications like penicillin, sulfa drugs, or aspirin. Insect venom from a bite or sting or natural rubber latex products, like gloves, also have been found to trigger allergic angioedema.

Medications

Some medications may cause swelling, even if a person is not allergic to them. This type of drug-induced angioedema is sometimes referred to as non-allergic 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. These medications increase the levels of bradykinin, a signaling molecule that prompts blood vessels to widen, thus lowering blood pressure. Bradykinin also increases the permeability of small blood vessels, which can lead to edema.

Another class of medications used to treat blood pressure, called angiotensin-receptor blockers (ARBs), also may cause angioedema. Generally, angioedema associated with ARBs is less severe and occurs earlier than angioedema caused by ACE inhibitors.

Several other types of medications can cause angioedema in some instances. These include certain antibiotics, statins — which are cholesterol-lowering medicines — and nonsteroidal anti-inflammatory drugs, known as NSAIDs, a medication class commonly used to control mild inflammation. NSAIDs include over-the-counter pain medicines like ibuprofen. The antidepressant buproprion, marketed as Wellbutrin, among other brand names, also has been found to cause angioedema in some instances.

Mutations

In hereditary angioedema (HAE), swelling occurs in part because of a genetic mutation that a person inherits from his or her biological parents. There are three different types of HAE, depending on the particular type of mutation one has.

Types 1 and 2 are caused by mutations in the SERPING1 gene, which codes for a protein called C1-inhibitor. This protein normally prevents a chain of chemical reactions in the blood known as the kallikrein-kinin system, which plays a role in inflammation, blood pressure control, and blood clotting. The system’s activation leads to the formation of bradykinin, which increases blood vessel leakiness and causes edema.

In type 1 HAE, mutations in the SERPING1 gene lower the levels of C1 inhibitor in the blood, whereas in type 2 they cause the protein to malfunction. In either case, the lack of a functional C1 inhibitor protein leads to the abnormal activation of the kallikrein-kinin system, and to the increased production of bradykinin, which increases blood vessel leakiness and causes edema.

Type 3 HAE is caused by mutations in the F12 gene. This gene codes for a protein called coagulation factor 12, which helps to regulate the activity of the immune system. Mutations in type 3 HAE cause this protein to be overactive, leading to increased inflammation and the production of bradykinin, and, therefore, to swelling.

Other causes

Sometimes, people without a mutation in the SERPING1 gene may have low levels of C1 inhibitor protein and develop another type of angioedema called acquired angioedema. In other cases, C1 inhibitor levels decrease as a result of another disease, like an infection or cancer. In yet other instances, the body’s immune system may mount an attack against C1 inhibitor proteins.

Regardless of the specific cause, low levels of C1 inhibitor lead to increased levels of bradykinin, which in turn lead to edema.

In cases in which angioedema develops without any clear cause, it is referred to as idiopathic angioedema. “Idiopathic” means “of unknown cause.” Such cases are treated in the same manner as those for which a cause is clear.

 

Last updated: June 17, 2021

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