Pathophysiology

Angioedema is a clinical symptom where certain parts of the body swell without warning. The swelling occur deeper under the skin or in the mucous tissues and is caused by tiny blood vessels leaking fluid into the surrounding tissues. The frequency, location and severity of swellings can vary considerably among patients and evolve over time. It may be triggered by allergies, genetic conditions, medications, or even occur without a known cause.

 

Common areas affected

Angioedema commonly affects the face, lips, and eyelids, as well as the tongue and throat—where swelling can be particularly dangerous if it interferes with breathing. It may also involve the hands, feet, or genital areas, and in some cases, the stomach, leading to sudden and severe abdominal pain.

How is angioedema different from hives?

Unlike hives (which present as red, itchy bumps on the skin), angioedema causes deeper swelling and may not itch at all. It primarily affects areas with loose skin or mucosal tissue.

Angioedema	Hives

 

Types and causes of angioedema

Angioedema can be broadly classified as histaminergic or bradykinin-mediated. The following table illustrates the clinical difference between the two:

Features	Histaminergic	Bradykinergic
Concomitant hives?	Yes, although not always	No
Any gastrointestinal involvement?	Uncommon, possible in cases of anaphylaxis	Yes, bowel edema can commonly present with gastrointestinal upset. In severe cases, can lead to bowel obstruction and ischemia
Any respiratory involvement?	Uncommon, but possible in cases of anaphylaxis	Possible, due to laryngeal edema
Duration of Symptoms	Shorter, usually subside within 1-3 days	Longer, can last for 3-4 days
Response to antihistamines, steroids or adrenaline	Yes	No
Response to bradykinin inhibitors or C1-INH replacement	No	Yes

 

When angioedema presents alongside urticaria, the following diagnostic framework applies :

Histaminergic angioedema

Histaminergic angioedema, often triggered by allergic reactions to food, drugs, or insect stings makes up about 70% of cases. It may also occur spontaneously and may be associated with chronic urticaria. It's usually—but not always—accompanied by hives and responds well to antihistamines, steroids, or mast cell-targeted treatments.

Hereditary angioedema (bradykinergic angioedema)

Hereditary angioedema (HAE) is a rare genetic disorder, typically caused by deficient or dysfunctional C1 inhibitor protein. Symptoms often begin in adolescence or early adulthood. Triggers include stress, trauma, infections, or medical procedures, though many attacks occur spontaneously. Unlike histaminergic angioedema, HAE does not involve hives and does not respond to antihistamines, corticosteroids, or mast cell-targeted therapies.

Drug-induced angioedema (bradykinergic angioedema)

Certain medications, especially ACE inhibitors, can cause angioedema through bradykinin buildup—not an allergic reaction. As a result, it typically does not respond to antihistamines, steroids, or other allergy treatments.

Spontaneous angioedema

Spontaneous angioedema refers to episodes of swelling with no identifiable cause. These episodes may involve either histaminergic or bradykinergic pathways.

 

Symptoms

The symptoms of histaminergic and bradykinin-mediated angioedema may differ.

Common symptoms

Puffy or swollen face, especially on the eyes and mouth, including lips and tongue

 

Only with histaminergic angioedema

Concomitant hives and an itchy rash

 

More commonly seen with bradykinergic angioedema

	Nausea or vomiting
	Breathing difficulties due to throat swelling
	Severe abdominal pain or cramps

 

Diagnosis

Diagnosing angioedema typically involves several steps:

	Medical history and physical examination The doctor will inquire about symptoms and family history. A physical examination will be conducted to check for swelling, rashes, or other related signs
	Allergy Testing (For histaminergic angioedema) Doctors may suggest allergy tests if angioedema is suspected to be caused by an allergic reaction. These can include skin tests or blood tests
	Blood Tests If bradykinergic angioedema (e.g. HAE) is suspected, doctors will assess the levels and functionality of a protein called C1 inhibitor through blood tests
	Genetic Testing Genetic testing may be performed to identify mutations in suspected cases of HAE

Treatment

Treatment strategies for angioedema vary depending on whether the condition is mediated by histamine or bradykinin. Patients with a history of spontaneous angioedema should avoid future use of ACE inhibitors, even if they previously tolerated the medication without issues.

Histaminergic angioedema

Histaminergic angioedema can be managed with medications that target mast cell activity, including antihistamines, a short course of corticosteroids, or biologic agents such as omalizumab. In severe or life-threatening cases—such as tongue swelling or airway obstruction—adrenaline should be administered promptly, ideally via an autoinjector, to rapidly alleviate symptoms.

Bradykinergic angioedema

Management of bradykinergic angioedema—particularly HAE—should be overseen by a Specialist in Immunology and Allergy. Acute HAE episodes require prompt treatment with HAE-specific therapies, such as bradykinin receptor antagonists or C1-inhibitor replacement. All patients with a confirmed diagnosis of HAE should have continuous access to on-demand medications to ensure timely intervention during attacks.