Angioedema causes

Angioedema, a form of swelling in the deep layers of the skin or mucous membranes, is most commonly caused by an allergic reaction. However, medications, genetics, and other health conditions may also cause it.

The disease occurs when small blood vessels become more permeable, or leaky, allowing fluid to escape and causing swelling under the skin. Facial swelling and swelling of the hands, feet, or genitals are common symptoms. Laryngeal edema, or swelling in the throat, is a potentially life-threatening complication that can impair breathing.

While all types of angioedema are characterized by swelling, each has a distinct underlying cause. Different angioedema triggers work in different ways, but the process generally involves one of two signaling molecules that increase blood vessel permeability — bradykinin or histamine. Correctly identifying the cause at the time of diagnosis is important for guiding the appropriate angioedema treatment strategy.

Common causes of angioedema

While there are several possible causes of angioedema, the swelling disorder most commonly occurs due to allergic reactions or as a side effect of certain medications.

Allergies

The most common cause of angioedema is an allergic reaction, a form of the disease called acute allergic angioedema.

In an acute allergic reaction, the immune system has an exaggerated inflammatory response against a harmless substance. As part of this response, mast cells release histamine, which increases blood vessel permeability and leads to swelling, often accompanied by hives.

Many substances can trigger allergies and lead to angioedema. Some specific acute allergic angioedema triggers include:

• foods, especially nuts, shellfish, milk, or eggs
• medications, such as antibiotics or nonsteroidal anti-inflammatory drugs (NSAIDs)
• insect venom from a bite or sting
• latex gloves, or other latex products

The central role of histamine in acute allergic angioedema is the reason why medications that block histamine signaling, called antihistamines, can usually treat it.

Medications

Some medications may cause swelling as a side effect, even if a person is not allergic to them, which is known as drug-induced nonallergic angioedema.

Rather than causing a histamine-mediated reaction, these medications, directly or indirectly, elevate bradykinin levels, which increase blood vessel permeability and cause angioedema without hives.

Drug-induced swelling has been associated with many medications, including:

• angiotensin-converting enzyme (ACE) inhibitors: used to treat high blood pressure
• angiotensin receptor blockers (ARBs): used to treat high blood pressure
• NSAIDs: used for pain and mild inflammation
• neprilysin inhibitors: often used in combination with ARBs for high blood pressure
• dipeptidyl peptidase-IV inhibitors: used to treat diabetes
• thrombolytic agents: used to treat blood clots
• statins: used to treat high cholesterol

ACE inhibitor angioedema is the most common type of drug-induced nonallergic angioedema. This class of medications directly prevents the breakdown of bradykinin.

ARBs, prescribed as an alternative to ACE inhibitors, less often cause angioedema, and when they do, the swelling attacks may be less severe. Scientists believe this may be because ARBs only indirectly affect bradykinin levels.

Less common causes of angioedema

In rarer cases, angioedema can be caused by genetic mutations or an immune system malfunction. There are also instances of angioedema where the specific underlying cause is not known.

Genetics

Hereditary angioedema (HAE) is a rare type of angioedema that’s caused by genetic mutations. They are usually inherited from a person’s biological parents, however, up to 25% of people with HAE develop these mutations spontaneously and have no family history of the disease.

Unlike angioedema related to allergies or medications, HAE causes chronic swelling episodes that may not be traceable to specific triggers. It is a bradykinin-mediated angioedema, and most HAE medications aim to reduce bradykinin levels to prevent swelling.

Genes that have been associated with HAE include:

• SERPING1
• F12
• PLG
• ANGPT1
• KNG1
• MYOF
• HS3ST6

HAE types 1 and 2 account for 90% to 95% of cases and are related to SERPING1 mutations. SERPING1 provides instructions for making the C1-inhibitor (C1-INH) protein, which helps regulate bradykinin production. Mutations either result in reduced C1-INH production (type 1) or in a dysfunctional C1-INH protein (type 2). Without enough working C1-INH, bradykinin levels rise, leading to swelling.

Mutations in other genes cause the rare HAE type 3. It is often linked to mutations in F12, which affects a protein that regulates bradykinin production. The exact mechanisms by which other genes cause disease are not fully understood.

Other causes

Acquired angioedema is a very rare condition marked by a C1-INH deficiency that results in excess bradykinin. While this is similar to HAE type 1, it results from other health conditions that arise later in life rather than from inherited mutations.

There are two types of acquired angioedema with different causes:

• type 1: Diseases that cause immune cells to grow out of control, including some autoimmune conditions and cancers, lead to the excessive activation of C1, a protein that C1-INH usually blocks. The body’s C1-INH stores are depleted as it attempts to correct rising C1 levels.
  
• type 2: The immune system mistakenly identifies C1-INH as a potential threat and launches an autoimmune attack against it.
  

Sometimes, doctors rule out all known explanations for angioedema and still can’t determine the underlying cause of swelling. This is referred to as idiopathic angioedema. It may be associated with histamines, bradykinin, or neither.

Risk factors

Several factors may increase a person’s risk of angioedema, though this varies by disease type.

• Allergies: People with known allergies have a higher risk of developing acute allergic angioedema. If a prior allergic reaction has triggered angioedema, later exposures to the same substance may also cause swelling.
• Medications: Patients taking ACE inhibitors or other medications associated with drug-induced nonallergic angioedema may be at an increased risk of swelling attacks.
• Demographic and lifestyle factors: Angioedema related to ACE inhibitor use is more common in older adults and Black people, with some studies also seeing it more often in women. Several studies show that smoking increases the risk of ACE inhibitor angioedema.
• Family history: A family history of HAE is a strong risk factor for this genetic type of angioedema. If a person with HAE has a biological child, there is a 50% chance their child will also have HAE. Genetics may also play a role in susceptibility to allergic or drug-induced angioedema.