Causes and Risk Factors of Angioedema

Allergy, Environment, and Genetics May All Play a Part

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Angioedema, swelling of the layer of tissue immediately beneath the skin, may be caused by an allergy, a drug reaction, one's environment, or even stress. It may also be hereditary, with a related gene mutation being passed down in families. The underlying mechanism in all cases is a malfunction of the immune system in which chemicals called histamine or bradykinins are abnormally released into the bloodstream. The area of the body affected—face, tongue, throat, arms, or legs—may provide a hint as to the cause, but not always.

angioedema causes

Common Causes

Acquired angioedema (AAE) can either be immunologic (related to allergy), non-immunologic (triggered by non-allergic causes), or idiopathic (of unknown origin). Unlike angioedema with a purely genetic cause (see below), some of the factors involved in these types may be modifiable.


Allergy is the most common cause of angioedema, triggered by a reaction to medications, food, insect stings, or other substances such as latex. The cause is considered immunologic because it involves an abnormal response of the immune system.

For reasons unknown, the body will sometimes mistake an otherwise harmless substance for a dangerous one and disperse large quantities of histamine into the bloodstream as a means of defense.

While histamines are meant to dilate blood vessels so that white blood cells can get closer to the site of an injury, when they are released in the absence of harm, they can trigger an array of adverse symptoms, including hay fever (allergic rhinitis), hives (urticaria), and allergic asthma.

Unlike other allergic reactions, angioedema occurs in subcutaneous tissue just beneath the top layer of skin or mucous membrane. The swelling will neither be itchy nor red and can last for several hours or days.

When the swelling finally stops, the skin will usually appear normal with no flaking, peeling, or bruising.


With immunologic angioedema, the cells responsible for instigating the attack are known as mast cells. Mast cells contain granules rich in histamine and, when instructed by the immune system to do so, will undergo a process called degranulation to release histamine into the system.

With non-immunologic angioedema, the immune system has nothing to do with the release. Instead, certain chemicals or physiological processes can induce mast cells to degranulate. Reactions will often occur in people with an underlying mast cell disorder, such as mastocytosis.

The drugs commonly associated with this include:

Other non-immunologic causes include blood transfusion, cancers like lymphoma, autoimmune diseases like lupus, and certain infections such as hepatitis, HIV, cytomegalovirus, and Epstein-Barr virus.

Certain physical stimuli such as heat, cold, excessive exercise, vibration, sun exposure, and even emotional stress have been known to cause angioedema.


With idiopathic angioedema, there will be no known cause or explanation for the sudden acute swelling. What makes the condition so vexing is that those affected are prone to recurrence, sometimes severe.

The face, mouth, and tongue were the areas most commonly affected. Overall, 55 percent of them reported receiving at least one course of high-dose corticosteroids to alleviate swelling. More concerning yet was the fact that 52 percent required at least one visit to the emergency room.


Hereditary angioedema (HAE) is considered an autosomal dominant disorder, meaning that you can inherit the problematic gene from just one parent. There are two types of HAE related to mutations in the SERPING1 gene and a third caused by the mutation of the F12 gene.

All three types cause the abnormal activation of the immune system and can cause swelling in all parts of the body. Where HAE differs from AAE is that the main culprit is not histamine. Rather, the attack will be instigated by another naturally occurring compound known as bradykinin.

Bradykinin, like histamine, causes the dilation of blood vessels but does so as a means to regulate body functions. For example, the body will release bradykinins to lower the blood pressure or to regulate respiratory or kidney function.

The abnormal release of bradykinins can trigger angioedema, most often of the legs, arms, genitals, face, lips, larynx, or gastrointestinal (GI) tract. A minor injury or episode of emotional stress can trigger an attack, but most occur without any known cause.

Angioedema of the GI tract can be severe, causing violent vomiting, intense pain, and dehydration from not being able to keep fluids down. If swelling occurs in the throat, it can be life-threatening.

Because ACE inhibitors (used to treat high blood pressure) work by sustaining bradykinin levels, they are among the most common cause of drug-induced angioedema (albeit with a different disease mechanism than opiates or aspirin).

HAE is considered rare, occurring in one of every 50,000 people, and is often only suspected if someone with angioedema does not respond to antihistamines.

Risk Factors

There is really no way to explain why some people get angioedema and others with the same health conditions or lifestyles don't. With that being said, you may be at higher risk if you have or have experienced any of the following:

You may be at higher risk for angioedema if you've experienced the following:

  • Drug reactions involving a rash or hives
  • Allergies involving hives
  • History of angioedema
  • A family history of hives or angioedema
  • Autoimmune disease such as lupus or Hashimoto's thyroiditis, for which angioedema is a possible symptom

If you or a loved one have suffered multiple bouts of angioedema, you may benefit from treatments that can help prevent future attacks. Options include a nightly dose of the antihistamine Zyrtec (cetirizine), if the cause is allergic, or immune-altering drugs such as Kalbitor (ecallantide) or Firazyr (icatibant).

Frequently Asked Questions

  • What causes angioedema?

    Angioedema is mostly caused by an allergy in which the immune system responds abnormally to an allergen and releases histamine into the bloodstream. Histamine triggers a cascade of inflammatory reactions, causing blood vessels to dilate and fluid to leak into underlying tissues. When this occurs in deeper subcutaneous and submucosal tissues, angioedema is the result.

  • What is hereditary angioedema?

    Hereditary angioedema is a genetic disorder characterized by the deficiency of C1 inhibitor, a substance the body uses to regulate a peptide known as bradykinin. Like histamine, bradykinin induces the dilation of blood vessels. Without C1 inhibitor to temper the response, the accumulation of bradykinin can trigger the excessive swelling of tissues.

  • Is angioedema autoimmune?

    Chronic and relapsing angioedema is often linked to autoimmune diseases, like lupus and Hashimoto’s thyroiditis. Some studies suggest that as many as 30% to 50% of idiopathic angioedema (meaning angioedema of unknown origin) may be associated with some form of autoimmune disease. In such cases, itchy hives (urticaria) will commonly accompany the deeper swelling of tissues.

  • How does pressure cause angioedema?

    Pressure angioedema develops when steady pressure applied to an area of skin causes the immediate or delayed swelling of deep tissues. Examples include wearing tight clothes or sitting for long periods of time. It is believed to be autoimmune in nature, during which sustained pressure causes mast cells found in vascular tissues to break open and release histamine. Extreme vibrations can do the same.

  • What drugs are most likely to cause angioedema?

    Angioedema is most closely linked to two classes of drugs:

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