Types of angioedema

Last updated Dec. 16, 2024, by Marisa Wexler, MS
Fact-checked by Joana Carvalho, PhD

 

There are several types of angioedema, a disease marked by swelling underneath the skin or in mucus membranes.

The different angioedema types are distinguished mainly by their underlying cause. Some forms are triggered by allergic reactions, while others occur due to genetic mutations, a malfunction of the immune system, or as a side effect of certain medications.

Angioedema treatment depends on the cause, duration, and severity of the condition.

Acute allergic angioedema

The most common type of angioedema — accounting for up to 70% of all cases — is acute allergic angioedema, in which swelling occurs as a result of an allergic reaction.

During an allergic reaction, the body’s immune system mistakenly recognizes a harmless external substance as a potential threat. These substances, often referred to as allergens, may include certain foods, medications, latex, pollen, and venom from insect bites and stings.

When this happens, immune cells release an inflammatory signaling molecule called histamine. Among other effects, histamine dilates blood vessels and increases their permeability, which can trigger swelling.

Timing of symptoms

Swelling in acute allergic angioedema usually occurs within minutes to about one to two hours after exposure to the allergen, and it may last a day or two without treatment. Symptoms such as hives and itching are generally more common in this form of acute angioedema than in other types of the disease.

Hereditary angioedema

Hereditary angioedema, or HAE, is a rare form of chronic angioedema that’s caused by genetic mutations. It is estimated to affect 1 out of every 50,000 to 150,000 people worldwide.

HAE-causing mutations are usually inherited from an individual’s biological parents, though in rarer cases they can arise spontaneously in people who don’t have a family history of the condition. HAE follows an autosomal dominant inheritance pattern, meaning that a single mutated gene copy is sufficient to trigger its onset. The disease affects people of all sexes and races equally.

This type of angioedema generally appears during adolescence or early adulthood in the form of recurrent swelling attacks or episodes of abdominal pain that can last a few days. HAE attacks may be preceded by early signs, which are called prodromal symptoms, that may include fatigue, muscle pain, feelings of pressure or tightness in the skin, a non-itchy rash, and mood changes. Unlike other forms of angioedema associated with allergic reactions, HAE is rarely accompanied by hives or itching.

HAE is divided into different types based on the specific disease-causing mutation a person carries. The most common, known as HAE types 1 and 2, are caused by mutations in the SERPING1 gene, while type 3 broadly encompasses all HAE cases caused by mutations in genes other than SERPING1.

Regardless of disease type, all cases are driven by higher-than-normal levels of bradykinin, a signaling molecule that causes blood vessels to dilate and increases their permeability, allowing fluid to escape to nearby tissues.

Angioedema medications are available for on-demand and preventive treatment of swelling attacks.

HAE type 1

The SERPING1 gene provides instructions for making a protein called C1 esterase inhibitor (C1-INH), which prevents bradykinin from being produced. In the presence of SERPING1 mutations, the resulting inhibitor deficiency causes bradykinin levels to rise too high.

HAE type 2

HAE type 2 accounts for about 15% to 20% of all HAE cases. In contrast to HAE type 1, C1-INH levels are normal or even high in type 2, but the protein itself is faulty and unable to function properly, so it cannot adequately regulate bradykinin production.

These HAE types can usually be confirmed with blood tests that measure the levels and activity of C1-INH, as well as of other proteins that are found at abnormal levels due to C1-INH deficiency.

HAE type 3

HAE type 3, also known as HAE with normal C1-INH, includes all cases of the disease caused by mutations in other genes.

The most well-known cases of HAE type 3 are associated with mutations in a gene called F12, which provides instructions for making a protein called coagulation factor XII that normally helps produce bradykinin. HAE-associated mutations cause this protein to be overactive, increasing bradykinin levels and triggering swelling. HAE associated with F12 mutations predominantly affects women, though there have also been documented cases of male patients with this form of HAE.

Other cases of HAE type 3 may be associated with mutations in other genes, such as PLG, ANGPT1, KNG1, MYOF, and HS3ST6, but these remain incompletely understood.

HAE type 3 is much rarer than types 1 and 2, and isn’t as well-understood. In type 3, C1-INH levels and activity are both normal, and patients can be definitively diagnosed only with genetic tests.

Drug-induced nonallergic angioedema

Drug-induced nonallergic angioedema refers to swelling that occurs as a side effect of certain medications.

This type of angioedema is most commonly associated with angiotensin-converting enzyme (ACE) inhibitors, a class of medications that are commonly used to lower blood pressure but also can increase bradykinin levels.

Angioedema affects up to 2.5% of patients taking ACE inhibitors, and is more common among those of African descent. People taking ACE inhibitors should be aware of this potential risk, especially because swelling can affect the throat and block the airways. If patients experience swelling in the neck or throat, they should seek immediate attention for this medical emergency.

Common triggers

Some commonly used ACE inhibitors that may trigger angioedema include lisinopril (marketed as Zestril, among other brand names) and enalapril (marketed as Vasotec and others).

Drug-induced nonallergic angioedema also may be associated with angiotensin receptor blockers, another class of medicines frequently used to treat high blood pressure. These medications include losartan (marketed as Cozaar and others) and valsartan (marketed as Diovan, among other brand names). In some cases, other types of medications, including nonsteroidal anti-inflammatory drugs may also trigger drug-induced nonallergic angioedema.

Timing of symptoms

Angioedema symptoms generally appear hours or days after exposure to the medication that triggers the condition, although they may arise much later. No specific diagnostic test can confirm the presence of this type of angioedema. If a patient shows signs of the condition and is known to have been taking medications that can cause angioedema as a side effect, discontinuing treatment with that drug is recommended.

Idiopathic angioedema

Idiopathic angioedema is a form of angioedema whose cause is not known despite thorough investigation. This type of angioedema is diagnosed when a person experiences recurrent or chronic episodes of swelling, and all other possible angioedema causes have been ruled out. In up to half of the cases, idiopathic angioedema occurs in people with underlying autoimmune disorders, such as lupus.

Most people diagnosed with idiopathic angioedema experience symptoms similar to those of allergy-related angioedema, where swelling is accompanied by other symptoms, such as itching or hives, and responds well to treatment with antihistamines. In rarer cases, idiopathic angioedema may be driven by other mediators, such as bradykinin, with symptoms similar to those of HAE.

Acquired angioedema

Acquired angioedema (AAE) is similar to HAE type 1 in that it is marked by abnormally low levels of the C1-INH protein. However, unlike HAE, where low C1-INH levels are caused by a genetic mutation that’s present from birth, AAE is marked by low C1-INH levels due to certain conditions that arise during a person’s lifetime. This type of angioedema is about 10 times less common than HAE, with estimates indicating it may affect 1 out of every 100,000 to 500,000 people.

AAE can be divided into two subtypes, depending on its specific cause:

• Type 1 AAE. This type develops in people with underlying disorders where immune cells grow excessively (lymphoproliferative disorders), including some autoimmune diseases and cancers. The abnormal growth of these immune cells leads to the irregular activation of certain inflammatory proteins, including C1 — a protein that, as its name suggests, is normally inhibited by C1-INH. As the body tries to regulate C1 levels, C1-INH is spent, ultimately leading to abnormally low C1-INH levels and swelling.
• Type 2 AAE. This type occurs as a result of an autoimmune disorder where the body’s immune system mistakes the C1-INH protein for an infectious threat and makes antibodies against it. This autoimmune attack ultimately prevents C1-INH from working as intended, setting the stage for swelling attacks.

Angioedema vs. hives

Angioedema and hives are two distinct forms of skin swelling. While angioedema is characterized by swelling in the deeper layers of the skin, hives are marked by swelling in superficial layers.

Angioedema and hives can co-occur in some cases, and the presence or absence of hives in people with angioedema can be helpful in identifying a person’s specific angioedema type. For instance, hives commonly affect people experiencing forms of angioedema associated with allergies, but are comparatively rare in people with HAE and other forms of angioedema mediated by bradykinin.

Difference between hives and angioedema

In hives, also referred to as urticaria, swelling appears as circular, oval, or worm-like shape wheals of varying sizes on the surface of the skin. The affected areas are usually darker than the surrounding skin. On people with paler skin, hives typically appear pink or reddish, whereas on dark-skinned individuals, they may look deep red or purple. A telltale sign of hives is that they are almost always itchy.

By contrast, swelling from angioedema is generally less defined than swelling from hives. Angioedema alone usually doesn’t cause dramatic skin discoloration or substantial itching, though areas affected by angioedema may feel warm, tender, or painful.

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