Types of angioedema
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There are several types of angioedema, a disease marked by swelling underneath the skin and/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.
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 may include foods (e.g., eggs, nuts, shellfish, milk), medications such as nonsteroidal anti-inflammatory drugs (e.g., aspirin) or certain antibiotics (e.g., penicillin), or latex.
When this happens, immune cells release an inflammatory signaling molecule called histamine which, among other effects, dilates blood vessels and increases their permeability, which can trigger swelling.
Swelling in acute allergic angioedema usually sets in within an hour of exposure to the allergen, the substance causing the allergic reaction, and it may last a day or two without treatment. Symptoms such as hives and itching are generally more common in this acute angioedema form 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 usually are 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 is a dominant genetic disorder, meaning that a single faulty gene copy is sufficient to trigger its onset. HAE affects people of all sexes and races equally.
This type of angioedema generally manifests during childhood 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 — what’s called prodromal symptoms — that may include fatigue, muscle aches, and a kind of rash that’s not itchy called erythema marginatum. 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 both caused by mutations in the SERPING1 gene, which provides instructions for making a protein called C1 esterase inhibitor (C1-INH).
The resulting deficiency in C1-INH activity leads to the excess production of a signaling molecule called bradykinin, which triggers swelling attacks.
HAE type 1
While HAE types 1 and 2 are both caused by mutations in the same gene, the consequences of those mutations on the C1-INH protein are distinct in each type. In HAE type 1, mutations in the SERPING1 gene impair protein production, causing the levels of C1-INH protein to dip too low. This is the most common form of HAE, accounting for 80% to 85% of all cases.
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 in HAE type 2, but the protein itself is faulty and unable to function properly, which also leads to reduced C1-INH activity.
HAE type 3
HAE type 3, sometimes called normal-C1-INH HAE, broadly encompasses all cases of HAE caused by mutations in genes other than SERPING1. These forms of HAE are much rarer than types 1 and 2, and aren’t so well understood. Unlike the two former types, C1-INH levels and activity are both normal in HAE type 3, and patients can only be diagnosed with genetic tests.
Some cases of HAE type 3 are associated with mutations in a gene called F12, which provides instructions for making a protein called coagulation factor 12 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 also have 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 and ANGPT1, but these remain incompletely understood.
Nonallergic angioedema
Nonallergic angioedema, also known as drug-induced 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 the levels of bradykinin.
Angioedema affects up to 2.5% of patients taking ACE inhibitors, and is more common among those of African descent. Patients taking ACE inhibitors should be aware of this potential risk, especially because swelling in the throat can block the airways and impair breathing, requiring immediate medical attention.
Some commonly used ACE inhibitors that may potentially trigger angioedema include benazepril (marketed as Lotensin), lisinopril (marketed as Zestril, among other brand names), and enalapril (marketed as Vasotec and others).
In rarer cases, nonallergic angioedema also may be associated with angiotensin receptor blockers, a 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).
Angioedema symptoms generally manifest in the first weeks or months of treatment with the medication that triggers the condition, although they may arise much later. There is no specific diagnostic test to confirm the presence of this type of angioedema. Suspicion may be triggered if a patient shows signs of the condition and is known to have been taking medications that can cause angioedema as a side effect. In such cases, discontinuing treatment with that drug is recommended.
Idiopathic angioedema
Idiopathic angioedema is a form of angioedema that lacks a specific known cause. 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 this disease form 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 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. But 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 a condition that develops during a person’s lifetime. This type of angioedema is about 10 times rarer 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 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 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 forms of skin swelling. While angioedema is characterized by swelling in the deeper layers of the the skin, hives are marked by swelling that occurs in the superficial layers of the skin.
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 the specific angioedema type a person has. For instance, hives commonly affect people experiencing forms of angioedema associated with allergies, but are comparatively rare in people with HAE.
In hives, also referred to as urticaria, swelling manifests in the form of 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 in 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.
Angioedema News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
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