Acquired angioedema

Last updated Sept. 20, 2024, by Marisa Wexler, MS
Fact-checked by Joana Carvalho, PhD

Acquired angioedema, sometimes abbreviated as AAE, is a rare type of angioedema that is commonly caused by another illness, such as cancer or an autoimmune disease. Like other angioedema types, AAE is marked by swelling attacks that can affect any part of the body, but most commonly occur in the extremities, genitals, or around the face.

Acquired angioedema is one of the rarest forms of angioedema, with estimates indicating it is about 10 times less common than hereditary angioedema (HAE), another rare form of the condition. Because the disease is rare and often goes undiagnosed, it’s difficult to establish a firm estimate of its prevalence. Available estimates suggest that AAE affects 1 of every 100,000 to 500,000 people.

While AAE can develop in people of any age, it is more likely to affect adults older than 40.

Causes

In AAE, swelling is driven by the excessive production of a signaling molecule called bradykinin. This molecule causes blood vessels to become more permeable, allowing fluid to leak into nearby tissues, and ultimately causing swelling.

The production of bradykinin is regulated by a protein called C1 esterase inhibitor (C1-INH), which normally acts as a brake to prevent the signaling molecule from being overproduced. In AAE, however, the activity of the C1-INH protein is very low, which causes bradykinin levels to rise and leads to swelling episodes.

There are two types of AAE. Their symptoms are indistinguishable, but the mechanisms leading to abnormally low C1-INH activity levels differ.

In acquired angioedema type 1, the activity of C1-INH is low because the protein is being consumed or spent at abnormally high rates. In these cases, the excessive consumption of C1-INH is generally driven by the overactivation of the classical complement pathway due to the presence of an underlying autoimmune disease or cancer.

The complement system is a part of the immune system that normally helps defend the body against invading microbes. The classical complement pathway, one of the main branches of the complement system, is typically activated by the interaction of immune complexes comprising an antibody bound to an antigen (a substance seen by the immune system as a potential threat) with a complement protein called C1q. This in turn leads to the formation of C1 esterase and to the activation of the complement system. C1-INH is the main protein that’s responsible for regulating the first steps of classical complement activation.

In patients with an underlying autoimmune disease or cancer, self-reactive antibodies or antibodies targeting malignant cells can bind to C1q, triggering complement activation. As the pathway gets progressively more activated, C1-INH is increasingly consumed to the point that patients develop C1-INH deficiency, setting the stage for AAE.

By contrast, in acquired angioedema type 2, the immune system erroneously makes antibodies that bind to C1-INH and prevent it from working normally.

In either case, C1-INH activity levels aren’t enough to appropriately control the production of bradykinin, which in turn drives swelling.

Acquired angioedema and cancer

It’s not always possible to pinpoint the exact acquired angioedema causes in each AAE patient. However, studies have shown that there’s a close link between acquired angioedema and cancer.

Most cases of AAE occur in people with lymphoproliferative disorders, or conditions marked by the excessive growth of immune cells. These include blood cancers, such as lymphoma and leukemia, as well as benign disorders marked by abnormal immune cell growth. In addition, certain solid cancers, such as renal or breast cancer, have been linked to acquired angioedema.

It is fairly common for symptoms of AAE to be among the first signs of an underlying cancer, so it’s generally recommended that people with acquired angioedema undergo monitoring for signs of a possible underlying disease.

AAE also can develop in association with autoimmune disorders, such as lupus, though this is not as common as AAE arising as a consequence of lymphoproliferative disorders.

While most cases of AAE are associated with cancer or another underlying illness, there are also some that develop in people with no evidence of other underlying health problems.

Symptoms

As with other forms of the condition, the hallmark acquired angioedema symptoms are attacks of swelling. These episodes can affect any part of the body, but most commonly occur in: 

• the extremities or limbs
• the face, lips, and/or throat
• the genitals
• the digestive tract.

Swelling in the digestive tract can lead to symptoms such as abdominal pain, nausea, and diarrhea. If swelling occurs in the throat, it can impair a person’s ability to breathe, which is life-threatening and constitutes a medical emergency requiring immediate medical treatment.

AAE is a form of chronic angioedema, meaning that swelling attacks can come and go over time. This is different from acute angioedema, in which swelling appears suddenly, but then stops once its underlying cause is addressed.

Swelling attacks in AAE tend to occur unpredictably. In some instances, sources of stress in the body — injuries, infections, medical procedures, or emotional stress, among others — may act as triggers for the attacks, but in many cases there is no clearly identifiable trigger. Without treatment, swelling attacks usually last two to five days.

Diagnosis

An acquired angioedema diagnosis is typically first suspected if a person is experiencing swelling attacks without any clear cause or trigger. This is especially the case if the patient is older, has no family history of angioedema, and/or is known to have an underlying lymphoproliferative or autoimmune disease.

If AAE is suspected, the first step toward reaching a diagnosis is to measure the levels of the C1-INH protein, along with those of a related protein called C4. In the classical complement pathway, C1-INH normally acts by blocking the activity of a protein that breaks down C4. For this reason, when the activity of C1-INH is reduced, C4 levels are usually low. If C4 levels are low but C1-INH levels are normal, then the activity of C1-INH should also be determined. If levels of both C1-INH and C4 are low, and/or if C4 levels are low and C1-INH activity is reduced, the patient is diagnosed with C1 inhibitor deficiency, meaning they either have AAE or HAE.

A deficiency in C1-INH is also the cause of most hereditary angioedema cases. However, because AAE is not associated with genetic mutations, these two angioedema types can be distinguished via genetic testing.

The differing types also can often be distinguished by testing for C1q, which is typically low in AAE, as a result of excessive complement activation, but not in HAE. If C1q levels are low, a diagnosis of AAE can be established. If C1q levels are normal but the patient does not have any identifiable mutation, AAE is usually the assumed diagnosis. Additional tests looking for antibodies targeting C1-INH also may help solidify the diagnosis of AAE in some cases.

If individuals are diagnosed with AAE, it’s generally recommended that they undergo additional tests looking for signs of a potential underlying lymphoproliferative or autoimmune disease.

Treatment

Because it’s driven by an overproduction of bradykinin, rather than an allergic reaction, swelling in AAE typically doesn’t respond to treatment with corticosteroids, antihistamines, or epinephrine, which are often used in other forms of angioedema.

Acquired angioedema treatment is generally more similar to that used for managing HAE. It often involves the use of C1-INH concentrates — purified forms of C1-INH isolated from the blood of healthy donors that are administered to patients to make up for the lack of the C1-INH protein. Examples include Berinert and Cinryze, which are both approved for HAE but have also been found to be effective in treating AAE.

Other approved treatments for HAE, including Firazyr (icatibant) and Kalbitor (ecallantide), which prevent bradykinin from binding to its receptor or reduce its production, also may be used to help manage AAE-related swelling, particularly in cases in which C1-INH concentrates prove to be ineffective.

If neither of these medications or C1-INH concentrates are available, fresh frozen plasma — which temporarily supplies patients with C1-INH and other blood components that break down bradykinin — may be used as an alternative.

Attenuated androgens, or medications that have a similar structure to the male sex hormone testosterone, and antifibrinolytics, which prevent blood clots from breaking down to keep bleeding under control, are sometimes used as prophylactic (preventive) therapies to help reduce the frequency of swelling attacks in HAE. Both of these treatment classes may also be used in AAE, though available data suggest that AAE patients usually respond better to antifibrinolytics, such as tranexamic acid and aminocaproic acid.

In patients with AAE associated with a cancer or autoimmune disease, treating the underlying disorder is often an effective step for managing angioedema and preventing swelling in the long term.

How does acquired angioedema differ from other types?

While all forms of angioedema are marked by bouts of swelling, the underlying causes are different, which sets AAE apart from other types.

Unlike drug-induced angioedema, which is also known as nonallergic angioedema, AAE does not arise as a side effect of medications. It’s also not caused by allergic reactions. Swelling in AAE also is typically not accompanied by urticaria, or hives, which distinguishes this type from acute allergic angioedema. Moreover, AAE usually has an identifiable cause, which sets it apart from idiopathic angioedema, where the underlying cause is unknown.

AAE is perhaps most similar to HAE, specifically HAE types 1 and 2, where swelling is also triggered by the overproduction of bradykinin due to reduced C1-INH activity.

The key distinction is that low C1-INH activity in HAE results from genetic mutations that a person is born with, so people with HAE will usually start to experience swelling attacks before they reach adulthood. By contrast, AAE develops over a person’s lifetime, usually due to other underlying health conditions that reduce C1-INH activity. That means that most people with AAE don’t start to experience swelling attacks until middle age or later.

Angioedema family history is another key difference between HAE and AAE. Because HAE has a genetic cause and is an hereditary form of angioedema, it is likely to manifest in multiple individuals from the same family, which doesn’t happen with AAE.

Symptoms of AAE and HAE are virtually identical, but some data suggests that specific patterns of swelling may differ between the two. Available evidence suggests that swelling in the digestive tract, which can cause abdominal pain, is more common in HAE patients, whereas swelling in or around the face may be more common in AAE.

Due to the extreme rarity of acquired angioedema, there is minimal data on life expectancy for patients. The prognosis for patients with AAE is variable, and tends to depend on the degree to which their underlying illness is controlled. Like other forms of angioedema, AAE can be fatal if swelling affects the airways and compromises breathing.

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