Angioedema

Introduction

Background

Many types of angioedema are described in the literature: hereditary angioedema (HAE) types I, II, and III; acquired angioedema; drug-induced angioedema (associated with angiotensin-converting enzyme [ACE] inhibitors and angiotensin II receptor blockers [ARBs]); urticaria-associated angioedema; and idiopathic angioedema. Most forms of angioedema are considered idiopathic. In general, angioedema can be categorized as with urticaria or without urticaria. Urticaria and angioedema are similar in pathogenesis; however, angioedema manifests deeper in mucosal tissue. The reaction is mast cell mediated when both are evident during clinical presentation. In this case, the patient describes subjective pruritus, often associated with hypersensitivity to an offending agent.

Ten percent of angioedema cases occur without urticaria and is considered to be kinin-mediated rather than a hypersensitivity reaction. Hereditary angioedema and acquired angioedema are associated with insufficient or dysfunctional C1 esterase inhibitor, resulting in increased circulation of vasoactive substances. This type of angioedema can be induced spontaneously, or it can be due to stress or medications; this type is highly associated with ACE inhibitors.

In general, angioedema is described as deep, subcutaneous, submucosal edema due to increased vascular permeability. It can manifest as an episodic or self-limiting event but can often be described as recurrent. Acute episodes may involve the skin, larynx, and buccal and gastrointestinal (GI) mucosa.

Pathophysiology

Angioedema without urticaria can be classified as hereditary angioedema (HAE) or acquired C1 inhibitory deficiency (AAE/ACID). Hereditary angioedema results from a quantitative or qualitative deficiency of the C1 esterase inhibitor (C1-INH) due to a defective C1NH gene.³ Type I is described as C1 esterase inhibitor deficiency. Type II is believed to be a dysfunction of C1 esterase inhibitor with normal-to-high circulating levels of the molecule. These two forms are not distinguishable clinically.

An additional type III HAE, occurring only in females, has also been described. In this case, there is also an abnormal functioning protein. Abdominal attacks are seen less frequently in this variant. Orofacial involvement seems to be the most common presentation of the type III sensitivity, making it very difficult to distinguish from types I and II. This type has also been associated with exogenous estrogen administration and pregnancy.

C1 esterase is a serine protease that is involved in the regulation of bradykinin, a potent vasoactive substance. Low levels of this protease results in the activation of the kallikrein-kinin system, the complement cascade, and the fibrinolytic system and results in the release of vasoactive peptides such as bradykinin, considered to be the most important regulatory complement involved in many molecular cascades.Release of vasoactive substances causes vasodilatation of endothelial cells as well as smooth muscle bowel contraction. This ultimately manifests in the common clinical presentation of the disease.

In the setting of hereditary angioedema, AAE, and ACE inhibitor – induced angioedema, bradykinin levels are directly elevated in the blood. ACE is naturally one of the inhibitors of bradykinin. With ACE inhibition, bradykinin levels are increased.

Acquired angioedema (ACID) is classified as type I or type II. It is a result of autoantibodies that act on the protease, thus increasing consumption of C1-INH. Clinically, it presents like hereditary angioedema.

The type I variant of acquired angioedema is associated with B-cell proliferative disorders. In this disease, there is hypercatabolization of C1-INH. Immunocomplexes are formed between antibodies and abnormal immunoglobulins on the cell surface of B cells. The complement cascade hyperreacts, producing large amounts of C1. C1-INH is then consumed on attempts to prevent the activation of the continuously activated C1. The relative deficiency of C1 inhibitor causes increased activation of the kallikrein-kinin system.Enzymatic cleavage by kallikrein is increased with consumption of kininogen and subsequently the production of bradykinin increases. The end result of this intricate molecular cascade is vasodilatation meditated by the interaction of kinins with endothelial cell receptors, B1R and B2R.

The type II variant of acquired angioedema is associated with autoantibodies (immunoglobulin G [IgG] and less often immunoglobulin M [IgM]) directed against the C1-INH molecule.Depletion of C1-INH results in the production of large amounts of bradykinin and other vasoactive substances, which causes the signs and symptoms of angioedema.

Angioedema associated with urticaria is a hypersensitivity to an offending agent. Histamine is released into the bloodstream, resulting in an increase in endothelial cell permeability. Angioedema, generalized urticaria, and, in severe cases, anaphylaxis will occur. The allergen binds to the mast cell, causing degranulation and histamine and tryptase release. Degranulations of mast cells have also been shown to be a direct result of anesthetics, contrast mediums, and opiates.

Autoantibodies against the mast cell IgE receptor or mast cell-bound IgE (or basophils) is another common cause of histamine release. Additionally, proteases may activate the complement cascade associated with c3a, c4a, and c5a, which are considered anaphylactoids, and result in increased capillary permeability and extravasation of fluid.⁷

Frequency

United States

Eighty-five percent of patients who experience angioedema not associated with urticaria have type I HAE. Approximately 1 out of 10,000 patients have recurrent angioedema classified as type I. Type II HAE occurs in 1 out of 50,000 people. Angioedema induced by ACE inhibitors occurs at a frequency of 0.1-0.7%.

Mortality/Morbidity

Morbidity and mortality are directly related to the severity of airway obstruction. Asphyxiation due to laryngeal edema yields a 3-40% mortality rate.

Race

No specific racial predilection exists for angioedema.

Sex

Women tend to have more occurrences of angioedema than men.

Age

Persons who are predisposed to angioedema have an increase in frequency of attacks after adolescence, with the peak incidence occurring in the third decade of life.

Clinical

History

• Hereditary angioedema (HAE), idiopathic angioedema, and drug-induced angioedema^1,2
  • Episodes consist of relapsing, self-limiting edema. All edema episodes are self-limiting, last for 1-7 days and are followed by a disease-free interval.
  • Edema may occur in the subcutaneous tissue, wall of the intestine, and larynx.
  • Abdominal pain attacks may present with or without nausea, vomiting, and ascites.
  • Skin swelling most frequently affects the lips, face, hands, feet, and genitalia.
  • Urticaria is generally not a clinical symptom.
  • Rare symptoms include episodes of tongue edema and swelling of the soft palate.
  • Local trauma (eg, dental procedure, tonsillectomy) or stress may be present in the patient's history.
  • The frequency and severity of the clinical symptoms are highly variable from patient to patient and even in the same patient with recurrent episodes.
  • The patient's history may include use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), or nonsteroidal anti-inflammatory drugs (NSAIDs).
  • Most of these edema episodes occur spontaneously without a recognizable external trigger.
• Urticaria-associated edema
  • Urticarial eruptions usually appear at intervals and are intensely pruritic.
  • Patients with angioedema or urticaria should be questioned in detail to identify the offending antigen (in cases of allergic angioedema).
  • History of atopy such as allergic rhinitis, asthma, and aspirin allergy should be sought, as these increase the risk of hypersensitivities.
  • Drugs associated with urticaria and angioedema include the following:
    • Radiocontrast agents
    • Opiates
    • Dextran
    • Aspirin
    • Nonsteroidal anti-inflammatory drugs
  • Common sources of antigens that cause urticaria and angioedema include the following:
    • Hymenoptera envenomations
    • Food allergies such as fresh berries, shellfish, fish, nuts, tomatoes, eggs, milk, chocolate, food additives, and preservatives, and exposure to water, sunlight, cold, or heat
    • Animal dander (from scales of shed skin)
  • Chronic urticaria (increasingly associated with Helicobacter pylori bacteria)

Physical

• General examination
  • Patients usually present with acute onset of well-demarcated cutaneous edema of distensible tissues (eg, lips, eyes, earlobes, tongue, uvula).
  • The face, extremities, and genitalia are most commonly affected.
• Airway assessment
  • First, determine airway patency.
  • Severe attacks can herald the onset of systemic anaphylaxis, characterized initially by dyspnea.
• Gastrointestinal (GI): Massive edema of the subcutaneous tissue in the abdominal region may present with abdominal distention and signs consistent with bowel obstruction.

Causes

• Mast cell–mediated angioedema/urticaria : This type of angioedema may be associated with antigen (allergy), food, drug, animal bites, stings (ie, Hymenoptera), preservatives, or food coloring. Note: Food coloring and preservatives may cause angioedema with or without urticaria.
• Hereditary angioedema
  • Hereditary angioedema (HAE) has an autosomal dominant pattern.
  • Types I and II are characterized by C1 esterase deficiency. The gene encoding for C1-INH is located in chromosome band 11q13.1.
  • Approximately 20–25% of cases are the result of spontaneous mutations without a family history of disease. In this disease, the gene is either nonfunctional and thus C1 esterase is not transcribed in adequate quantities, as in type I, or there is synthesis of normal quantities of an abnormally functioning C1-INH protein, as in type II.
  • Type III is characterized by C1 esterase dysfunction. Symptoms occur during the first 2 decades of life.
• Acquired angioedema
  • This type of angioedema usually occurs in the fourth decade of life.
  • Acquired angioedema is often associated with autoimmune diseases and lymphoproliferative disorders.
• Drug-induced angioedema
  • ACE inhibitors precipitate attacks by directly interfering with the degradation of bradykinin, thereby potentiating its biological effect.
  • Other drugs may precipitate attacks by effects on arachidonic acid metabolism (eg, aspirin, NSAIDs, ARBs, opiates, antibiotic, any compound that is a cyclooxygenase inhibitor).
• Physically induced angioedem
  • Physical agents, such as cold, heat pressure, vibration, and ultraviolet radiation, can cause angioedema. This manifestation may occur with or without urticaria.
  • Cold-induced angioedema and urticaria have been reported in association with cryoglobulins, cold agglutinin disease, cryofibrinogenemia, and paroxysmal cold hemoglobinuria.
• Idiopathic angioedema: Most commonly, the cause is idiopathic.