Idiopathic angioedema

 

Idiopathic angioedema, sometimes referred to as chronic idiopathic angioedema, is a form of angioedema that has no obvious cause.

Similar to other types of angioedema, its hallmark symptom is swelling in the deeper layers of the skin or in mucus membranes, which most commonly occurs in the face, limbs, and extremities.

Causes and triggers

The word idiopathic refers to conditions whose cause is not known despite thorough investigation. Idiopathic angioedema therefore refers to a type of angioedema that has an unknown cause and where no obvious trigger for swelling can be identified.

While the underlying cause cannot be identified, doctors can perform tests to learn which molecular mechanisms are driving the swelling. Depending on the mechanism, idiopathic angioedema can be classified as histaminergic or nonhistaminergic.

Histamine is an inflammatory signaling molecule that drives swelling during allergic reactions, which are the cause of allergic angioedema. As the name suggests, swelling is also driven by histamine in people with histaminergic idiopathic angioedema, even though there isn’t a clear trigger for an allergic reaction.

This type of idiopathic angioedema is usually identified based on whether a patient’s swelling responds to high-dose antihistamine treatment, that is, medications that block the activity of histamine. The prevalence of histaminergic idiopathic angioedema is higher than that of the nonhistaminergic form.

In nonhistaminergic idiopathic angioedema, swelling is not driven by histamine and, as a result, antihistamines are not effective. Instead, it may be caused by activation of mast cells, the immune cells involved in allergic reactions, through mediators other than histamine. Or it may be caused by abnormal bradykinin signaling, which is also implicated in other forms of angioedema, namely hereditary angioedema and acquired angioedema.

BradykininIn is a signaling molecule that causes blood vessels to become more permeable, which sometimes can cause fluid to leak into surrounding tissues and drive swelling. In people with hereditary or acquired angioedema, bradykinin levels are elevated due to a C1 inhibitor deficiency, that is, abnormally low levels of a bradykinin-regulating protein called C1 inhibitor. In turn, the exact reason for abnormal bradykinin signaling in bradykinin-mediated idiopathic angioedema is not known.

Symptoms

The defining symptom of idiopathic angioedema is swelling. It commonly occurs in the face, hands, arms, legs, and trunk. In some cases, swelling around the mouth and throat can block the airways and compromise breathing. This is a medical emergency and patients should seek immediate treatment if it occurs.

Idiopathic angioedema is typically considered a form of chronic angioedema, meaning patients will have multiple swelling attacks over time without any clear cause or trigger. This distinguishes idiopathic angioedema from forms of acute angioedema, where swelling does not recur spontaneously once it has been resolved.

People with idiopathic angioedema may also have itchy welts (urticaria, also known as hives), similar to those with chronic idiopathic urticaria — a condition marked by itchy hives without a clear cause, which can also be accompanied by angioedema.

This symptom is more commonly seen in people whose swelling is caused by histamine or other forms of mast cell activation. People whose angioedema is mediated by bradykinin rarely experience hives.

Idiopathic angioedema symptoms may also include issues that are sometimes observed in other types of angioedema, depending on which parts of the body are affected by swelling. For example, swelling around the digestive tract can lead to symptoms of abdominal pain and diarrhea.

Diagnosis

Diagnosing idiopathic angioedema is largely a process of exclusion, where other causes of angioedema are first ruled out before a diagnosis can be established.

Angioedema-like swelling is usually visible and clinicians can generally tell if someone is experiencing angioedema from a physical exam. If a patient shows signs of angioedema, a doctor will ask for tests to determine its underlying cause. These can include allergy and blood tests, as well as genetic testing.

By definition, if a cause is identified, the patient does not have idiopathic angioedema and will instead be diagnosed with another form of angioedema. But if no clear cause can be identified, and all other forms of angioedema have been ruled out, then a diagnosis of idiopathic angioedema can be made.

Though there aren’t any hard definitions, as a general rule patients may be considered to have idiopathic angioedema if they experience three or more swelling attacks within six to 12 months and no clear cause is identified for those attacks.

Treatment

No medications are specifically approved to treat idiopathic angioedema. Generally, the goal in treating this type of angioedema is to control swelling, and medicines that are approved for other angioedema types are often also employed to help manage idiopathic angioedema.

Idiopathic angioedema treatment for people whose swelling is mediated by histamine tends to include medicines used to ease inflammation and treat allergies in allergic angioedema. These include:

• antihistamines
• corticosteroids
• epinephrine, the active agent in Epi-Pens, in serious cases.

If a person fails to respond to high-dose antihistamines, the next treatment that should be tested is omalizumab, an antibody-based therapy that’s approved as Xolair for some allergy-related conditions. If the patient also fails to improve with omalizumab, excluding the involvement of mast cells in the swelling attacks, then a bradykinin-mediated angioedema can be considered.

Finally, treatment for idiopathic angioedema mediated by bradykinin may include medicines that are approved to treat hereditary angioedema, such as:

• Firazyr (icatibant), which prevents bradykinin from interacting with its receptor and triggering swelling
• Kalbitor (ecallantide), which inhibits the activity of an enzyme involved in bradykinin production
• concentrated forms of C1 inhibitor, including Berinert and Cinryze, which provide a version of the C1 inhibitor protein to normalize bradykinin levels.

Living with idiopathic angioedema

Living with idiopathic angioedema can be stressful, especially considering the unpredictable nature of the condition and the inability to determine its exact triggers. It’s important to practice self-care and seek support when needed.

Clinicians who are familiar with angioedema can help patients find useful resources about the condition. Support groups and patient organizations can offer a sense of community and provide patients with strategies to improve daily life.

For patients who have found treatments that are consistently effective for controlling their swelling, it’s a good idea to keep those medications close at hand in case they are needed. General good-health practices, such as getting enough rest and eating a healthy balanced diet, are an important part of managing life with any chronic health condition.

Can triggers be avoided?

Because idiopathic angioedema causes are not known, it’s often unclear what specific triggers drive swelling attacks, making it difficult for patients to avoid them. That said, some patients may find that certain things tend to trigger swelling, such as stress, anxiety, infections, or exposure to extreme temperatures.

For people with idiopathic angioedema, it can be a good idea to keep detailed notes about what happened right before each attack, including places they went and things they ate or touched. That way, if there is a pattern or a consistent trigger, it can be more easily identified.

It may also be advisable that patients try to avoid potential triggers for other types of angioedema. For example, a class of blood pressure-lowering medications called angiotensin converting enzyme (ACE) inhibitors are a notable cause of drug-induced nonallergic angioedema, so patients with idiopathic angioedema who need medications to control their blood pressure may want to consider alternatives.

Allergies are also a common angioedema trigger, so patients may want to avoid exposure to common allergens that may act as swelling triggers. These may include certain foods like shellfish and nuts, certain medications like antibiotics and aspirin, and latex products.

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