eMedicine Specialties > Allergy and Immunology > Urticaria and Angioedema

Angioedema

Author: Huamin Henry Li, MD, PhD,, Director of Immunology, Institute for Asthma and Allergy
Contributor Information and Disclosures

Updated: Dec 21, 2009

Introduction

Background

Angioedema (AE) was initially described by Dr. John L Milton as giant urticaria in 1876.¹ It was later regarded as a separate clinical entity after Sir William Olser described hereditary angioneurotic edema in 1888.² Only recently, the term angioneurotic edema has been changed to angioedema. The condition is the result of swelling of cutaneous and/or mucosal tissue due to vascular leakage.³ It is usually nonpitting and nonpruritic. The area of involvement is often skin-colored or slightly erythematous. Local pain is variable when skin is involved. However, abdominal pain (even severe pain) is common when the gastrointestinal tract is affected. Angioedema can also be life-threatening when the airway is involved.

Angioedema is often associated with urticaria. In fact, almost 50% of patients who present with urticaria also have angioedema.⁴ When angioedema is not accompanied by concurrent urticaria, the etiologies are often very different. This article concentrates on angioedema without urticaria. Hereditary angioedema (HAE), a special type of angioedema without urticaria due to C1-esterase inhibitor (C1-INH) deficiency, is discussed in a separate article (Hereditary Angioedema).

Pathophysiology

The swelling of the affected area in angioedema is a result of the fast onset of increase of local vascular permeability in submucosal and subcutaneous tissue. Numerous vasoactive mediators are involved in this process. Multiple cellular components and mediators are all implicated in the process of different forms of angioedema.

The IgE-mediated mast cell activation and degranulation is a key element of an allergic reaction. Anaphylaxis and urticaria are discussed in separate articles. The non–IgE-mediated mast cell activation/mediator release may explain the phenomena of certain autoimmune mediated and idiopathic urticaria and angioedema. However, other cells (eg, macrophage, dendritic cells, lymphocytes, monocytes, eosinophils, endothelial cells) may also be involved. Plasma and tissue factors are also found to play an important role in certain forms of angioedema. Bradykinin, certain complement factors, contact system components, estrogen, and certain protease deficiencies and genetic polymorphisms have also been found to play a role in certain types of angioedema.

Urticaria is often discussed together with angioedema. In many cases, the conditions are remarkably similar, both in underlying etiologies and clinical management strategies. However, angioedema usually involves a deeper layer of skin (reticular dermis) and/or subcutaneous or submucosal tissue, whereas urticaria affects a more superficial layer of skin (papillary dermis and mid dermis). In addition, mucosal involvement is common in angioedema but not in urticaria. Pruritus is a major feature of urticaria but is less troublesome or absent in angioedema. Mild to severe pain or tenderness has been observed often in angioedema but not in urticaria.

Frequency

United States

Angioedema (excluding HAE or acquired angioedema [AAE]) may affect 10-20% of the population at some time in their lives. The great majority of chronic angioedema is idiopathic. HAE is a rare condition, found in 1 per 10,000 to 150,000 persons. By some estimates, HAE may account for 15,000-30,000 emergency department visits annually. AAE is even more uncommon; until 1997, fewer than 50 cases had been reported in the literature. The incidence of angioedema with the use of ACE inhibitors is reported to be 1-2 cases per 1000 persons.

International

International occurrence rates are believed to be similar to those reported in the United States.

Mortality/Morbidity

Angioedema is one of the most troubling complications of an acute allergic reaction. In one study, 69.4% of 138 patients who had anaphylaxis were found to have angioedema.⁵ In addition to the disfiguring appearance, patients often report local pain and discomfort. When angioedema affects the hands and feet, walking and many other daily activities are impaired. Abdominal pain is common when the gastrointestinal tract is involved; it can be severe and disabling.

Angioedema can be life-threatening when it involves the larynx and upper airway, leading to trouble breathing, asphyxia, and even death. Of angioedema presented in the emergency room, 10-20% of cases are considered to be life-threatening.^6,7

Race

African Americans are more susceptible to angioedema induced by ACE inhibitors. Compared with white persons, the adjusted relative risk is about 3.0 to 4.5.^7,8 Other forms of angioedema have no clear association between race and the disease frequency or severity.

Sex

Estrogen may exacerbate certain forms of angioedema. In HAE, affected women tend to have more frequent attacks and run more severe clinical courses. HAE type III is found predominantly in women. In these patients, taking oral contraceptives that contain estrogen is often a triggering factor for angioedema.⁹ Chronic idiopathic angioedema is more common in females than in males. Other types of angioedema do not show a strong sex preponderance.

Age

Angioedema can affect patient of all ages. Allergic reactions to food are more common in children. For patients with HAE, the onset of symptoms is often around puberty. The average age for angioedema induced by ACE inhibitors is 60 years. Idiopathic angioedema is more common among those aged 30-50 years than among other age groups.

Clinical

History

Patients usually describe swelling of the face (eg, eyelids, lips), tongue, hands, and feet. It can be acute or chronic, and each episode of angioedema may last a few hours to a few days. A local burning sensation and pain can be observed without pronounced itchiness or local erythema. Abdominal pain can sometimes be the only presenting symptom of angioedema. Throat tightness, voice changes, and trouble breathing may indicate airway involvement.

For acute and new-onset angioedema, special attention should be directed to the potential relationship with food or drug intake, insect stings, or other unusual exposures. For chronic and recurrent cases, ask the patient about potential triggers, medication use and associated medical history, family history, and past evaluation.

Physical

For skin involvement, examination can easily identify areas of swelling with or without erythematous skin, often with ill-defined margins. Some cases of angioedema occur in patients with urticaria.

The examination of abdominal (intestinal mucosal) angioedema can be challenging. The patient may have changes in bowel sounds and diffuse or localized tenderness. Some cases may resemble an acute abdomen.

Uvula or tongue swelling can be visualized directly. However, a laryngoscopy is needed to assess laryngeal or vocal cord involvement.

Causes

Angioedema can be categorized as allergic, pseudoallergic, nonallergic, or idiopathic. More than 40% of chronic angioedema is idiopathic. All cases of angioedema pose significant diagnostic and treatment challenges.

Allergic angioedema

• Allergic angioedema is often associated with urticaria. It is typically observed within 30 minutes to 2 hours after exposure to the allergen (eg, food, drug, venom, latex).
• More detailed description of this condition can be found in the eMedicine articles on anaphylaxis and urticaria.

• Pseudoallergic angioedema is not IgE-mediated. However, its clinical course and presentation is very similar to allergic angioedema. Typical examples are angioedema induced by nonsteroidal anti-inflammatory drugs (NSAIDs) and intravenous contrast material; aspirin (ASA) is the most common culprit.
• True IgE-mediated reactions to ASA or other NSAIDs are very rare. The angioedema (with or without urticaria) reflects the pharmacologic properties of the drugs. By inhibiting cyclooxygenase (COX), ASA and NSAIDs lead to overproduction of proinflammatory and vasoactive leukotrienes. COX-2 inhibitors and acetaminophen do not usually cause angioedema.

Nonallergic angioedema

• Nonallergic angioedema does not involve IgE or histamine; urticaria is generally not associated with this type of angioedema.
• Hereditary angioedema (HAE) is perhaps the prototype of this type of angioedema. Decreased functional C1-INH production leading to unchecked bradykinin production are believed to be the fundamental changes in HAE types I and II.¹⁰ Acquired angioedema (AAE) also has decreased C1-INH function due to autoantibody production or accelerated consumption of C1-INH. Please see the article on HAE for additional details on these conditions.
• ACE inhibitor–induced angioedema (AIIA) is bradykinin-mediated, as are HAE and AAE. Unlike most drug hypersensitivities or reactions, the onset of AIIA can occur months or years after starting the medicine.^11,12 Therefore, it can easily be overlooked as a cause for angioedema. AIIA is not drug-specific. As illustrated in the image below, ACE inhibitors interfere with the degradation of bradykinin, a potent vasoactive nonapeptide.

Idiopathic angioedema

• The cause of idiopathic angioedema is often unclear. The exact mechanisms are often elusive. Some may be associated with urticaria. Based on responses to medication, many of these cases are thought to be mediated by mast cell activation, albeit IgE-independent.
• Physical urticaria/angioedema: The exact etiologies are not certain. Common triggers include heat, cold, emotional stress, and exercise. Nonspecific mast cell activation and degranulation are suspected causes.
• Autoimmune conditions: Thyroid autoantibodies are found in 14-28% of patients with chronic urticaria/angioedema, and IgG autoantibodies are found in 30-50% of patients with chronic urticaria/angioedema. In affected individuals, autoantibody (IgG) has been found to crosslink FceRI on mast cells, resulting in mast cell activation and release of histamine, cytokines, and other proinflammatory mediators. Immunomodulatory drugs have been shown to be beneficial for this type of angioedema.
• Infections: The exact link between infection and angioedema is quite vague at best. Helicobacter pylori infection has been found to be associated with HAE exacerbation. Treatment of H pylori infection has led to clinical improvement of chronic urticaria and angioedema.¹³ Systemic viral, bacterial, or parasitic infection may stimulate the immune system and cause improper activation or inflammatory changes.
• Estrogen-dependent angioedema: C1 INH functions normally in estrogen-dependent angioedema.¹⁴ This has been proposed as HAE type III. The exact mechanism of angioedema in these patients is still unclear.¹⁵ In some of the affected patients, FXII point mutation results in a gain of function that can potentially affect the metabolism of bradykinin.
• Gleich syndrome: Patients with this syndrome exhibit elevated eosinophil with angioedema. It responds well to corticosteroids. It is thought to be related to hypereosinophilic syndrome. In addition to the elevated eosinophils count, IgG autoantibody against endothelial cells has been identified.

Table 1 compares different types of angioedema.

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